Preparation of 3-amino(or carbamyl)-5-(pyridinyl)-2(1H)-pyridinones

ABSTRACT

Compounds useful as cardiotonic agents are 1-R-3-Q-5-PY-2(1H)-pyridinones (I) where R is hydrogen, lower-alkyl or lower-hydroxyalkyl, Q is amino (preferred), lower-alkylamino, di-(lower-alkyl)amino or NHAc, Ac is lower-alkanoyl or lower-carbalkoxy, and PY is 4- or 3- or 2-pyridinyl or 4- or 3- or 2-pyridinyl having one or two lower-alkyl substituents. The corresponding compounds where Q is nitro, carbamyl, cyano, halo or hydrogen are useful as intermediates and those where Q is hydrogen or cyano also are useful as cardiotonic agents. Said compounds are prepared: by reacting α-PY-β-(R 1  R 2  N)acrolein (II) with malonamide to produce 1,2-dihydro-2-oxo-5-PY-nicotinamide (Ia) and reacting Ia with a reagent capable of converting carbamyl to amino to produce 3-amino-5-PY-2(1H)-pyridinone (Ib); by reacting II or α-PY-malonaldehyde (II&#39;) with α-cyanoacetamide to produce 1,2-dihydro-2-oxo-5-PY-nicotinonitrile (III) and partially hydrolyzing III to produce Ia; and, by heating 1,2-dihydro-2-oxo-5-PY-nicotincic acid (IV) with a mixture of concentrated sulfuric acid and concentrated nitric acid to produce 3-nitro-5-PY-2(1H)-pyridinone (Ic) and then either reducing Ic to produce Ib or first reacting Ic with an alkylating agent to produce 1-R&#39;-3-nitro-5-PY-2(1H)-pyridinone (Id) and reducing Id to produce 1-R&#39;-3-amino-5-PY-2(1H)-pyridinone (Ib) where R&#39; is lower-alkyl or lower-hydroxyalkyl. Other derivatives of I where Q is amino are shown.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a division of copending application Ser. No.937,120, filed Aug. 28, 1978, and now U.S. Pat. No. 4,137,233, issuedJan. 30, 1979 in turn, a division of copending application Ser. No.876,571, filed Feb. 10, 1978 and now U.S. Pat. No. 4,137,233, issuedJan. 30, 1979, in turn, a division of application Ser. No. 818,724,filed July 25, 1977 and now U.S. Pat. No. 4,107,315, issued Aug. 15,1978 in turn, a continuation-in-part of its copending application Ser.No. 707,235, filed July 21, 1976 and now U.S. Pat. No. 4,072,746, issuedFeb. 7, 1978, in turn, a continuation-in-part of its copendingapplication Ser. No. 621,763, filed Oct. 14, 1975, and now U.S. Pat. No.4,004,012, issued Jan. 18, 1977.

BACKGROUND OF THE INVENTION

(a) Field of the Invention

This invention relates to 3-amino-5-(pyridinyl)-2(1H)-pyridinones,useful as cardiotonic agents, to their preparation and to intermediatesused therein.

(b) Description of the Prior Art

There is no teaching in the prior art of any cardiotonically activecompounds having any chemical structure comparable to or suggestive ofthe instantly claimed compounds.

The Lesher and Gruett British Pat. No. 1,322,318, published July 4,1973, discloses as intermediates 1,2-dihydro-2-oxo-6-(4- or3-pyridinyl)-nicotinonitrile, 6-(4- or 3-pyridinyl)-2(1H)-pyridinone and6-(4- or 3-pyridinyl)-2-pyridinamine.

The Brundage and Lesher U.S. Pat. No. 3,838,156, issued Sept. 24, 1974,discloses as intermediates 1,2-dihydro-2-oxo-6-Q'"-nicotinic acids whereQ'" is 4(or 3)-pyridinyl or 4(or 3)-pyridinyl having one or twoloweralkyl substituents.

The Shionogi and Co. Japanese Patent 20,295/67, published Oct. 11, 1967,shows 1-(x'-amino-2'-pyridinyl)-2-pyridinones as having "analgesic andantiphlogistic activity". Specifically shown is1-(5'-amino-2'-pyridinyl)-2-pyridinones.

SUMMARY OF THE INVENTION

In a composition aspect, the invention relates to1-R-3-Q-5-PY-2(1H)-pyridinones where R is hydrogen, loweralkyl orlower-hydroxyalkyl, Q is carbamyl and halo, and PY is 4- or 3- or2-pyridinyl or 4- or 3- or 2-pyridinyl having one or two lower-alkylsubstituents. The compounds where Q is carbamyl are useful asintermediates in the preparation of the compounds where Q is amino andthose where Q is halo are useful as intermediates in the preparation ofthe compounds where Q is lower-alkylamino and di-(loweralkyl)amino.

Another composition aspect of the invention relates to1-R-3-Q-5-PY-2(1H)-pyridinones where Q is hydrogen and R and PY aredefined as above. These compounds not only are useful as intermediatesin preparing the corresponding compounds where Q is amino, but also theysurprisingly have been found to have useful cardiotonic activity; and,further, they surprisingly have been found to have useful bronchodilatoractivity.

The invention in a process aspect resides in the process of producing3-amino-5-PY-2(1H)-pyridinone (Ib) which comprises reacting α-PY-β-(R₁R₂ N)acrolein (II) with malonamide to produce1,2-dihydro-2-oxo-5-PY-nicotinamide (Ia) and reacting Ia with a reagentcapable of converting carbamyl to amino to produce Ib, where PY isdefined as above, and R₁ and R₂ are each lower-alkyl.

In another process aspect the invention comprises reacting eitherα-PY-β-(R₁ R₂ N)acrolein (II) or α-PY-malonaldehyde (II') withα-cyanoacetamide to produce 1,2-dihydro-2-oxo-5-PY-nicotinonitrile (III)and partially hydrolyzing III to produce1,2-dihydro-2-oxo-5-PY-nicotinamide (Ia), where PY, R₁ and R₂ are eachdefined as above.

In another process aspect the invention comprises first heating1,2-dihydro-2-oxo-5-PY-nicotinic acid (IV) with a mixture ofconcentrated sulfuric acid and concentrated nitric acid to produce3-nitro-5-PY-2(1H)-pyridinone (Ic) and then either reducing Ic toproduce 3-amino-5-PY-2(1H)-pyridinone (Ib) or first reacting Ic with analkylating agent of the formula R'-An to produce1-R'-3-nitro-5-PY-2(1H)-pyridinone (Id) and reducing Id to produce1-R'-3-amino-5-PY-2(1H)-pyridinone, where PY has the meaning givenabove, R' is lower-alkyl or lower-hydroxyalkyl and An is an anion of astrong inorganic acid or an organic sulfonic acid.

In another process aspect the invention comprises reacting1-R-3-amino-5-PY-2(1H)-pyridinone with a lower-alkanoylating agent orlower-carbalkoxylating agent to produce 1-R-3-Q'-5-PY-2(1H)-pyridinone(Ie), where PY and R have the meanings given hereinabove and Q' is NHAcwhere Ac is lower-alkanoyl or lower-carbalkoxy, respectively.

In another process aspect the invention comprises heating1,2-dihydro-2-oxo-5-PY-nicotinonitrile (III) or1,2-dihydro-2-oxo-5-PY-nicotinic acid (IV) with an aqueous mineral acid,preferably aqueous sulfuric acid, to produce 5-PY-2(1H)-pyridinone (Ie)upon respective hydrolysis of III and decarboxylation of IV, reacting Iewith halogen, preferably bromine or chlorine, to produce thecorresponding 3-halo-5-PY-2(1H)-pyridinone (If) and reacting If with aloweralkylamine or a di-(lower-akyl)amine to produce the corresponding3-(lower-alkylamino)-5-PY-2(1H)-pyridinone (Ig-1) or3-[di-(lower-alkyl)amino]-5-PY-2(1H)-pyridinone (Ig-2).

An alternative process aspect of the invention for preparing Ig-1 orIg-2 comprises reacting 3-amino-5-PY-2(1H)-pyridinone with one or twomolar equivalents of a lower-alkylating agent. A preferred embodiment ofthis alternative process comprises reacting3-amino-5-PY-2(1H)-pyridinone with a methylating mixture of formic acidand formaldehyde to produce 3-dimethylamino-5-PY-2(1H)-pyridinone wherePY is defined as above for I.

Another composition aspect of the invention relates to a cardiotoniccomposition for increasing cardiac contractility, said compositioncomprising a pharmaceutically-acceptable carrier and, as the activecomponent thereof, a cardiotonic 1-R-3-Q-5-PY-2(1H)-pyridinone where PYand R are defined as above and Q is hydrogen.

In a method aspect, the invention relates to a method for increasingcardiac contractility which comprises the administration of a medicamentcomprising a pharmaceutically-acceptable carrier and, as the activecomponent thereof, an effective amount of a cardiotonic1-R-3-Q-5-PY-2(1H)-pyridinone where PY and R are defined as above and Qis hydrogen.

Another composition aspect of the invention relates to di-(lower-alkyl)N-[1,2-dihydro-2-oxo-5-PY-3-pyridinyl]-aminomethylenemalonate where PYis defined as above. These compounds also have been found to have usefulcardiotonic activity.

Another composition aspect of the invention relates to a cardiotoniccomposition for increasing cardiac contractility, said compositioncomprising a pharmaceutically-acceptable carrier and, as the activecomponent thereof, a cardiotonic di-(lower-alkyl)N-[1,2-dihydro-2-oxo-5-PY-3-pyridinyl]aminomethylenemalonate, where PYis defined as above.

In another method aspect, the invention relates to a method forincreasing cardiac contractility which comprises the administration of amedicament comprising a pharmaceutically-acceptable carrier and, as theactive component thereof, an effective amount of a cardiotonicdi-(lower-alkyl)N-[1,2-dihydro-2-oxo-5-PY-3-pyridinyl]aminomethylenemalonate where PY isdefined as above.

DETAILED DESCRIPTION INCLUSIVE OF PREFERRED EMBODIMENTS

In a composition aspect the invention resides in the compounds havingformula I ##STR1## where PY is 4- or 3- or 2-pyridinyl or 4- or 3- or2-pyridinyl having one or two lower-alkyl substituents, R is hydrogen,lower-alkyl or lower-hydroxyalkyl, and Q is carbamyl or halo, orpharmaceutically-acceptable acid-addition salt thereof. The compounds offormula I where Q is amino, lower-alkylamino, di-(lower-alkyl)amino, orNHAc are useful as cardiotonic agents, as determined by standardpharmacological evaluation procedures. The compounds of formula I whereQ is carbamyl are useful as intermediates for preparing the compoundswhere Q is amino and those where Q is halo are useful as intermediatesin the preparation of the compounds where Q is lower-alkylamino anddi-(lower-alkyl)amino. Preferred embodiments are those of formula Iwhere Q is carbamyl, R is hydrogen and PY is 4-pyridinyl or 3-pyridinyl.A particularly preferred embodiment is3-carbamyl-5-(4-pyridinyl)-2(1H)-pyridinone, that is,1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotinamide.

Other composition aspects resides in the compounds having formula Iwhere Q is hydrogen, or pharmaceutically-acceptable acid-addition saltthereof. These compounds not only are useful as intermediates forpreparing the compounds of formula I where Q is amino, but also areuseful as cardiotonic agents and, also, are useful as bronchodilators asdetermined by standard pharmacological procedures. Preferred embodimentsare those where PY is 4-pyridinyl or 3-pyridinyl.

In a process aspect the invention resides in the process of producing3-amino-5-PY-2(1H)-pyridinone (Ib) which comprises reacting α-PY-β-(R₁R₂ N)acrolein (II) with malonamide to produce1,2-dihydro-2-oxo-5-PY-nicotinamide (Ia) and reacting1,2-dihydro-2-oxo-5-PY-nicotinamide (Ia) with a reagent capable ofconverting carbamyl to amino to produce 3-amino-5-PY-2(1H)-pyridinone(Ib), where PY is defined as in I above, and R₁ and R₂ are eachlower-alkyl, preferably methyl or ethyl. Other process aspects of theinvention reside in each of two said steps, that is, the preparation ofIa from II and the conversion of Ia to Ib.

In another process aspect the invention resides in the process ofreacting either α-PY-β-(R₁ R₂ N)acrolein (II) or α-PY-malonaldehyde(II') with α-cyanoacetamide to produce1,2-dihydro-2-oxo-5-PY-nicotinonitrile (III) and partially hydrolyzing1,2-dihydro-2-oxo-5-PY-nicotinonitrile (III) to produce1,2-dihydro-2-oxo-5-PY-nicotinamide (Ia), where PY is defined as in Iabove, and R₁ and R₂ are each loweralkyl, preferably methyl or ethyl.

In another process aspect the invention resides in the process ofproducing 3-amino-1-R-5-PY-2(1H)-pyridinone (Ib) which comprises firstheating 1,2-dihydro-2-oxo-5-PY-nicotinic acid (IV) with a mixture ofconcentrated sulfuric acid and concentrated nitric acid to produce3-nitro-5-PY-2(1H)-pyridinone (Ic) and then either reducing3-nitro-5-PY-2(1H)-pyridinone (Ic) to produce3-amino-5-PY-2(1H)-pyridinone (Ib) or first reacting3-nitro-5-PY-2(1H)-pyridinone (Ic) with an alkylating agent of theformula R'-An to produce 1-R'-3-nitro-5-PY-2(1H)-pyridinone (Id) andreducing 1-R'-3-nitro-5-PY-2(1H)-pyridinone (Id) to produce1-R'-3-amino-5-PY-2(1H)-pyridinone (Ib), where R and PY have the samemeanings given hereinabove for formula I, and R' is loweralkyl orlower-hydroxyalkyl and An is an anion of a strong inorganic acid or anorganic sulfonic acid. Other process aspects of the invention reside inthe conversion of IV to Ic and in the two-step conversion of IV to Ic toId.

The above process aspects of the invention are illustrated by thefollowing flow sheet which also shows the conversion of1,2-dihydro-2-oxo-5-PY-nicotinonitrile (III) to1,2-dihydro-2-oxo-5-PY-nicotinic acid (IV) by hydrolysis with aqueoussulfuric acid: ##STR2##

Alternatively, 1,2-dihydro-2-oxo-5-PY-nicotinonitrile (III) is convertedto 3-nitro-5-PY-2(1H)-pyridinone (Ic) via 5-PY-2(1H)-pyridinone (Ie) byfirst refluxing III with aqueous sulfuric acid to produce1,2-dihydro-2-oxo-5-PY-nicotinic acid (IV) and then refluxing IV insolution (without isolation) to produce Ie which is then heated with amixture of concentrated sulfuric acid and concentrated nitric acid toproduce Ic.

In another process aspect the invention resides in the process ofproducing 1-R-3-Q'-5-PY-2(1H)-pyridinone (Ie) which comprises reacting1-R-3-amino-5-PY-2(1H)-pyridinone (Ib) with a lower-alkanoylating agentor lower-carbalkoxylating agent, where PY and R have the meanings givenhereinabove for the compounds of formula I and Q' is NHAc where Ac islower-alkanoyl or lower-carbalkoxy, respectively.

In another process aspect the invention comprises the steps of heating1,2-dihydro-2-oxo-5-PY-nicotinonitrile (III) or1,2-dihydro-2-oxo-5-PY-nicotinic acid (IV) with an aqueous mineral acid,preferably aqueous sulfuric acid, to produce 5-PY-2(1H)-pyridinone (Ie)upon hydrolysis of III and decarboxylation of IV, reacting Ie withhalogen, preferably bromine or chlorine, to produce the corresponding3-halo-5-PY-2(1H)-pyridinone (If) and reacting If with alower-alkylamine (R₁ NH₂) or a di-(lower-alkyl)amine (R₁ R₂ NH) toproduce the corresponding 3-(lower-alkylamino)-5-PY-2(1H)-pyridinone (Igwhere R₁ is lower-alkyl and R₂ is hydrogen) or3-[di-(lower-alkyl)amino]-5-PY-2(1H)-pyridinone (Ig where each of R₁ andR₂ is lower-alkyl). This process aspect of the invention also comprisessaid individual steps and combinations thereof.

An alternative process aspect of the invention for preparing Igcomprises reacting 3-amino-5-PY-2(1H)-pyridinone with one or two molarequivalents of a lower-alkylating agent. A preferred embodiment of thisalternative process comprises reacting 3-amino-5-PY-2(1H)-pyridinonewith a methylating mixture of formic acid and formaldehyde to produce3-dimethylamino-5-PY-2(1H)-pyridinone where PY is defined as above forI.

The above additional process aspects of the invention are illustrated bythe following additional flow sheet which also shows the conversion of3-amino-5-PY-2(1H)-pyridinone (Ib) to di-(lower-alkyl)N-[1,2-dihydro-2-oxo-5-PY-3-pyridinyl]aminomethylenemalonate (V):##STR3## In the formulas of above flow sheet PY has the meaning givenhereinabove for formula I, R₁ is lower-alkyl, R₂ is hydrogen orlower-alkyl, and R₃ and R₄ are each lower-alkyl.

Another composition aspect of the invention resides in a cardiotoniccomposition for increasing cardiac contractility, said compositioncomprising a pharmaceutically-acceptable inert carrier and, as theactive component thereof, an effective amount of a cardiotonic1-R-3-Q-5-PY-2(1H)-pyridinone having the formula of claim 1 where PY andR are each defined as in formula I and Q is hydrogen, orpharmaceutically-acceptable acid-addition salt thereof.

A method aspect of the invention resides in the method for increasingcardiac contractility in a patient requiring such treatment whichcomprises administering orally or parenterally in a solid or liquiddosage form to such patient an effective amount of a cardiotonic1-R-3-Q-5-PY-2(1H)-pyridinone having the formula of claim 1 where PY andR are each defined as in formula I and Q is hydrogen, orpharmaceutically-acceptable acid-addition salt thereof.

The compounds of formula I where Q is cyano and their use as cardiotonicagents are disclosed and claimed in copending application Ser. No.621,763, filed Oct. 14, 1975, now U.S. Pat. No. 4,004,012, issued Jan.18, 1977.

The compounds of formula I where Q is amino, lower-alkylamino,di-(lower-alkyl)amino or NHAc where Ac is lower-alkanoyl orlower-carbalkoxy, as well as their use as cardiotonic agents, and alsothe intermediate nitro compounds of formula I where Q is nitro, aredisclosed and claimed in copending application Ser. No. 707,235, filedJuly 21, 1976.

Another composition aspect of the invention relates to di-(lower-alkyl)N-[1,2-dihydro-2-oxo-5-PY-3-pyridinyl]aminomethylenemalonate (V) wherePY is defined as above, or pharmaceutically-acceptable acid-additionsalt thereof. These compounds also have been found to have usefulcardiotonic activity. A preferred embodiment of this composition aspectis diethylN-[1,2-dihydro-2-oxo-5-4-(pyridinyl)-3-pyridinyl]aminomethylenemalonate.

Another composition aspect of the invention relates to a cardiotoniccomposition for increasing cardiac contractility, said compositioncomprising a pharmaceutically-acceptable inert carrier and, as theactive component thereof, an effective amount of a cardiotonicdi-(lower-alkyl)N-[1,2-dihydro-2-oxo-5-PY-3-pyridinyl]aminomethylenemalonate (V) wherePY is defined as above, or pharmaceutically-acceptable acid-additionsalt thereof. A preferred embodiment of this composition aspect isdiethylN-[1,2-dihydro-2-oxo-5-(4-pyridinyl)-3-pyridinyl]aminomethylenemalonate.

In another method aspect, the invention relates to a method forincreasing cardiac contractility in a patient requiring such treatmentwhich comprises the administering orally or parenterally in a solid orliquid dosage form to such a patient an effective amount of acardiotonic di-(lower-alkyl)N-[1,2-dihydro-2-oxo-5-PY-3-pyridinyl]aminomethylenemalonate (V) wherePY is defined as above, or pharmaceutically-acceptable acid-additionsalt thereof.

The term "lower-alkyl" as used herein, e.g., as one of the meanings forR or as a substituent for PY in formula I or as used in the Qsubstituent when lower-alkylamino or di-(lower-alkyl)amino, means alkylradicals having from one to six carbon atoms which can be arranged asstraight or branched chains, illustrated by methyl, ethyl, n-propyl,isopropyl, n-butyl, sec.-butyl, tert.-butyl, isobutyl, n-amyl, n-hexyl,and the like.

The term "lower-hydroxyalkyl", as used herein, e.g., as one of themeanings for R in formula I, means hydroxyalkyl radicals having from twoto six carbon atoms and having its hydroxy group and its free valencebond (or connecting linkage) on different carbon atoms, illustrated by2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl,2-hydroxy-2-methylpropyl, 3-hydroxypropyl, 2-hydroxy-1,1-dimethylethyl,4-hydroxybutyl, 5-hydroxyamyl, 6-hydroxyhexyl, and the like.

Illustrative of PY in formula I where PY is 4- , 3- or 2-pyridinylhaving one or two lower-alkyl substituents are the following [note that"pyridinyl" as used herein is the same as "pyridyl", the former nowbeing the preferred term used in Chemical Abstracts]:2-methyl-4-pyridinyl, 2,6-dimethyl-4-pyridinyl, 3-methyl-4-pyridinyl,2-methyl-3-pyridinyl, 6-methyl-3-pyridinyl (alternatively named2-methyl-5-pyridinyl), 4-methyl-2-pyridinyl, 6-methyl-2-pyridinyl,2,3-dimethyl-4-pyridinyl, 2,6-dimethyl-4-pyridinyl,4,6-dimethyl-2-pyridinyl, 2-ethyl-4-pyridinyl, 2-isopropyl-4-pyridinyl,2-n-butyl-4-pyridinyl, 2-n-hexyl-4-pyridinyl, 2,6-diethyl-4-pyridinyl,2,6-diethyl-3-pyridinyl, 2,6-di-isopropyl-4-pyridinyl,2,6-di-n-hexyl-4-pyridinyl, and the like.

The term "lower-alkanoyl", as used herein, e.g., as one of the meaningsfor Ac in formula I, means alkanoyl radicals having from one to sixcarbon atoms, including the straight- and branch-chained radicals,illustrated by formyl, acetyl, propionyl (N-propanoyl), butyryl(n-butanoyl), isobutyryl (2-methyl-n-propanoyl) and caproyl(n-hexanoyl).

The term "lower-carbalkoxy", as used herein, e.g., as one of themeanings for Ac in formula I, means carbalkoxy radicals where the alkoxyportion can be straight- or branch-chained and has from one to sixcarbon atoms, as illustrated by carbomethoxy, carbethoxy,carbo-n-propoxy, carbisopropoxy, carbo-n-butoxy, carbo-tert.-butoxy andcarbo-n-hexoxy.

The compounds of formulas I and V are useful both in the free base formand in the form of acid-addition salts; and, both forms are within thepurview of the invention. The acid-addition salts are simply a moreconvenient form for use; and in practice, use of the salt forminherently amounts to use of the base form. The acids which can be usedto prepare the acid-addition salts include preferably those whichproduce, when combined with the free base, pharmaceutically-acceptablesalts, that is, salts whose anions are relatively innocuous to theanimal organism in pharmaceutical doses of the salts, so that thebeneficial cardiotonic properties inherent in the free base are notvitiated by side effects ascribable to the anions. In practicing theinvention, it was found convenient to form the sulfate, phosphate,methanesulfonate or lactate. However, other appropriatepharmaceutically-acceptable salts within the scope of the invention arethose derived from mineral acids such as hydrochloric acid and sulfamicacid; and organic acids such as acetic acid, citric acid, tartaric acid,ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid,cyclohexylsulfamic acid, quinic acid, and the like, giving thehydrochloride, sulfamate, acetate, citrate, tartrate, ethanesulfonate,benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate,respectively.

The acid-addition salts of said basic compound are prepared either bydissolving the free base in aqueous or aqueous-alcohol solution or othersuitable solvents containing the appropriate acid and isolating the saltby evaporating the solution, or by reacting the free base and acid in anorganic solvent, in which case the salt separates directly or can beobtained by concentration of the solution.

Although pharmaceutically-acceptable salts of said basic compounds arepreferred, all acid-addition salts are within the scope of ourinvention. All acid-addition salts are useful as sources of the freebase form even if the particular salt per se is desired only as anintermediate product as for example when the salt is formed only forpurposes of purification or identification, or when it is used as anintermediate in preparing a pharmaceutically-acceptable salt by ionexchange procedures.

The molecular structures of the composition aspects (I) of the inventionwere assigned on the basis of evidence provided by infrared,ultraviolet, nuclear magnetic resonance and mass spectra, bychromatographic mobilities, and, by the correspondence of calculated andfound values for the elementary analyses for representative examples.

The manner of making and using the instant invention will now begenerally described so as to enable a person skilled in the art ofpharmaceutical chemistry to make and use the same, as follows:

The preparation of 1,2-dihydro-2-oxo-5-PY-nicotinamide (Ia) by reactingα-PY-β-(R₁ R₂ N)acrolein (II) with malonamide is carried out preferablyby mixing the reactants in a suitable solvent in the presence of a basiccondensing agent. The reaction is conveniently run using a lower-alkanolas the solvent, preferably methanol or ethanol, and an alkalilower-alkoxide, preferably sodium methoxide or sodium ethoxide,respectively, as the basic condensing agent. In practicing theinvention, the reaction was carried out in refluxing methanol usingsodium methoxide. Other basic condensing agents include sodium hydride,lithium diethylamide, lithium diisopropylamide, and the like, in anaprotic solvent, e.g., tetrahydrofuran, acetonitrile, ether, benzene,dioxane, and the like.

The above-noted intermediate α-PY-β-(R₁ R₂ N)acroleins (II) aregenerally known and are prepared by conventional methods. For example,II is produced by reacting an α-PY-acetic acid with the reaction productobtained by reacting dimethylformamide with a phosphorus oxyhalide,preferably the oxychloride or oxybromide. The reaction ofdimethylformamide with the phosphorus oxyhalide is run preferably below10° C. and the resulting reaction product is heated with the α-PY-aceticacid at about 50° to 80° C. to produce II. The intermediate α-PY-aceticacids are generally known compounds which are prepared by conventionalmethods; for example, they are produced readily by heating thecorresponding acetylpyridine of the formula PY--COCH₃ with sulfur andmorpholine to produce the corresponding PY-thioacetomorpholinamide whichon refluxing with 12 N hydrochloric acid yields the α-PY-acetic acid,e.g., α-(3-ethyl-4-pyridinyl)acetic acid, is produced from4-acetyl-3-ethylpyridine via 3-ethyl-4-pyridinylthioacetomorpholinamide[Jain et al., Indian Journal of Chemistry 10, 455 (1972)]. Theacetylpyridines, i.e., PY--COCH₃, also are generally known compoundswhich are prepared by conventional procedures, e.g., production from thecorresponding cyanopyridines, i.e., PY-CN, [Reilly Tar & Chem. Corp.British Pat. No. 920,303, published Mar. 6, 1963; Case et al., J. Am.Chem. Soc. 78, 5842 (1956)].

The conversion of 1,2-dihydro-2-oxo-5-PY-nicotinamide (Ia) to3-amino-5-PY-2(1H-pyridinone (Ib) is carried out by reacting Ia with areagent capable of converting carbamyl to amino. This reaction isconveniently run by heating an aqueous mixture containing an alkalimetal hypohalite, preferably hypobromite or hypochlorite, and Ia, andthen acidifying the reaction mixture, preferably with an aqueous mineralacid, e.g., hydrochloric acid. The reaction can be carried out fromabout 25° C. to 100° C., preferably about 60° C. to 100° C.

The reaction of α-PY-β-(R₁ R₂ N)acrolein (II) with α-cyanoacetamide toproduce 1,2-dihydro-2-oxo-5-PY-nicotinonitrile (III) is carried outpreferably by mixing the reactants in a suitable solvent in the presenceof a basic condensing agent. The reaction is conveniently run using alower-alkanol as a solvent, preferably methanol or ethanol, and analkali lower-alkoxide, preferably sodium methoxide or sodium ethoxide,respectively, as the basic condensing agent. In practicing theinvention, the reaction was carried out in refluxing methanol usingsodium methoxide. Other basic condensing agents include sodium hydride,lithium diethylamide, lithium diisopropylamide, and the like, in anaprotic solvent, e.g., tetrahydrofuran, acetonitrile, ether, benzene,dioxane, and the like.

The reaction of α-PY-malonaldehyde (II') with α-cyanoacetamide toproduce 1,2-dihydro-2-oxo-5-PY-nicotinonitrile (III) is carried out byheating the reactants in the presence of a catalytic condensing agent,preferably morpholine or piperidine and/or its acetate. The reaction isconveniently carried out by refluxing a benzene solution containing thereactions in the presence of morpholine, piperidine, morpholine acetate,piperidine acetate or mixtures thereof, preferably with a waterseparator attached to the reaction vessel to collect the water producedby the reaction.

The partial hydrolysis of 1,2-dihydro-2-oxo-5-PY-nicotinonitrile (III)to produce 1,2-dihydro-2-oxo-5-PY-nicotinamide (Ia) is carried out byheating III with concentrated sulfuric acid. While the reaction isconveniently and preferably run by heating the reactions on a steambath, the temperature range for the reaction can vary from about 25° to135° C. Alternatively, the conversion of III to Ia can be carried out byheating III at about 100° to 175° C. with polyphosphoric acid for aboutone to five hours.

The hydrolysis of 1,2-dihydro-2-oxo-5-nicotinonitrile (III) to produce1,2-dihydro-2-oxo-5-PY-nicotinic acid (IV) is conveniently run byheating III on a steam bath with an aqueous mineral acid, preferably 50%sulfuric acid.

The conversion of 1,2-dihydro-2-oxo-5-PY-nicotinic acid (IV) to3-nitro-5-PY-2(1H)-pyridinone (Ic) is carried out by heating IV with amixture of concentrated sulfuric acid and concentrated nitric acid. Theheating of the reactants is conducted at about 60° to 100° C.,preferably at about 70° to 90° C. Although it might be presumed that thenicotinic acid (IV) is first decarboxylated to produce the corresponding3-unsubstituted-5-PY-2(1H)-pyridinone, which is then nitrated at the3-position, it is noted, as shown above, that heating the correspondingnicotinonitrile (III) with concentrated sulfuric acid alone results inpartial hydrolysis yielding the corresponding nicotinamide (Ia).

Alternatively, 1,2-dihydro-2-oxo-5-PY-nicotinonitrile (III) is readilyconverted step-wise to 3-nitro-5-PY-2(1H)-pyridinone (Ic) by firstheating III with aqueous sulfuric acid for a longer period (supra) thanrequired to form 1,2-dihydro-2-oxo-5-PY-nicotinic acid (IV) whereupon IVis first formed and then is decarboxylated on continued heating toproduce 1,2-dihydro-2-oxo-5-PY-pyridine which is then nitrated under thesame reaction conditions noted above for converting IV to Ic, that is,by heating 1,2-dihydro-2-oxo-5-PY-pyridine with a mixture ofconcentrated sulfuric acid and concentrated nitric acid to produce3-nitro-5-PY-2(1 H)-pyridinone (Ic).

The reaction of 3-nitro-5-PY-2(1H)-pyridinone (Ic) with alower-alkylating agent to produce 1-R'-3-nitro-5-PY-2(1H)-pyridinone(Id) is generally carried out by reacting Ic with a lower-alkyl or alower-hydroxyalkyl ester of a strong inorganic acid or an organicsulfonic acid, said ester having the formula R'-An, where An is an anionof a strong inorganic acid or an organic sulfonic acid, e.g., chloride,bromide, idodide, sulfate, methanesulfonate, benzenesulfonate, andpara-toluenesulfonate (or tosylate), and R' is lower-alkyl orlower-hydroxyalkyl. This alkylation is preferably run using a slightexcess of the alkylating agent although equimolar quantities givesatisfactory results. The chloride, bromide, iodide or tosylate ispreferred because of the ready availability of the requisite lower-alkylhalides or tosylates; and, the reaction is carried out preferably in thepresence of an acid-acceptor. The acid-acceptor is a basic substancewhich preferably forms freely water-soluble by-products easily separablefrom the product of the reaction, including for example, sodiumhydroxide, potassium hydroxide, sodium carbonate, potassium carbonate,sodium alkoxides, potassium alkoxides, sodium amide, and the like. Theacid-acceptor picks up the hydrogen halide or tosylate (or HAn) which issplit out during the course of the reaction. The reaction is preferablycarried out in the presence of a suitable solvent which is inert underthe reaction conditions, e.g., a solvent such as lower-alkanol, acetone,dioxane, dimethylformamide, dimethyl sulfoxide, hexamethylphosphoramide, or a mixture of solvents, e.g., a mixture of water and alower-alkanol. The reaction is generally carried out at a temperaturebetween about room temperature (about 20°-25° C.) and 150° C.,preferably heating on a steam bath in a stirred mixture ofdimethylformamide and anhydrous potassium carbonate.

The reaction of 3-nitro-5-PY-2(1H)-pyridinone or1-R'-3-nitro-5-PY-2(1H)-pyridinone (Id) to produce1-R-3-amino-5-PY-2(1H)-pyridinone (Ib) can be carried out either bycatalytic or chemical reductive means. In prracticing the invention, thehydrogenation of Ic or Id to produce Ib was conveniently run in asuitable solvent, e.g., dimethylformamide, in the presence of ahydrogenation catalyst, e.g., palladium-on-charcoal, at room temperature(about 20° to 25° C.) until the uptake of hydrogen ceased. Othersuitable solvents include tetrahydrofuran, dioxane, methanol, ethanol,water (containing a base, e.g., sodium hydroxide, potassium hydroxide,triethylamine, etc.), and the like. Other suitable hydrogenationcatalysts include Raney nickel, platinum oxide, and the like. Chemicalreducing agents useful in the reduction of Ic and Id to produce Ibinclude iron and acetic acid, zinc and hydrochloric acid, and the like.

The acylation of 1-R-3-amino-5-PY-2(1H)-pyridinone (Ib) to produce thecorresponding 1-R-3-Q'NH-5-PY-2(1H)-pyridinone (Ie) is carried out byreacting Ib with a lower-alkanoylating agent or a lower-carbalkoxylatingagent, e.g., a lower-alkanoyl halide, preferably chloride, alower-alkanoic anhydride, a lower-alkyl haloformate, and the like,preferably in the presence of an acid-acceptor, as illustratedhereinabove for the lower-alkylation reaction. Thelower-carbalkoxylation reaction can be carried out step-wise by firstreacting the 1-R-3-amino-5-PY-1-R-2(1H)-pyridinone (Ib) with1,1'-carbonyldiimidazole in the presence of a suitable solvent, e.g.,dimethylformamide, to produceN-(1-R-1,2-dihydro-2-oxo-5-PY-3-pyridinyl)-imidazole-1-carboxamide whichis then heated with a lower-alkanol to yield the correspondinglower-alkyl N-(1-R-1,2-dihydro-2-oxo-5-PY-3-pyridinyl)carbamate.

The reaction of 5-PY-2(1H)-pyridinone (Ie) with halogen to produce3-halo-5-PY-2(1H)-pyridinone (If) is carried out preferably by mixingthe reactants in an appropriate solvent inert under the reactionconditions, a preferred solvent being acetic acid. The reaction isconveniently run at room temperature or by heating at moderatetemperatures up to about 100° C. Preferred halogens are bromine andchlorine. Any inert solvent can be used, e.g., dimethylformamide,chloroform, ethanol, and the like.

The reaction of 3-halo-5-PY-2(1H)-pyridinone (If) with alower-alkylamine or a di-(lower-alkyl)amine to produce the corresponding3-(lower-alkylamino)-5-PY-2(1H)-pyridinone (Ig; R₁ is lower-alkyl and R₂is hydrogen) or 3-[di-(lower-alkyl)amino]-5-PY-2(1H)-pyridinone (Ig; R₁and R₂ are each lower-alkyl), respectively, is carried out by heatingthe reactants in an autoclave at about 100°-180° C., preferably about125°-160° C. and preferably using a suitable solvent, e.g., water,dimethylformamide, dioxane, 1,2-dimethoxyethane, and the like, ormixtures thereof.

A preferred method of preparing the3-dimethylamino-5-PY-2(1H)-pyridinone is carried out by reacting3-amino-5-PY-2(1H)-pyridinone (Ib) with a mixture of formaldehyde andformic acid to effect dimethylation of the primary 3-amino group. Thisreaction is conveniently carried out by refluxing the3-amino-5-PY-2-(1H)-pyridinone (Ib) with an excess each of formaldehyde,preferably an aqueous solution thereof, and formic acid, preferably morethan a two-fold molar excess of each.

The following examples will further illustrate the invention without,however, limiting it thereto.

A. 1,2-DIHYDRO-2-OXO-5-(PYRIDINYL)NICOTINONITRILES A-1.1,2-Dihydro-2-oxo-5-(4-pyridinyl)nicotinonitrile

A reaction mixture containing 35 g. ofα-(4-pyridinyl)-β-dimethylaminoacrolein, 21.6 g. of sodium methoxide,500 ml. of methanol and 17 g. of α-cyanoacetamide was heated to refluxwith stirring whereupon an exothermic reaction ensued sufficient tocause the reaction mixture to reflux without the use of external heat.The reaction mixture was then refluxed with stirring for an additionalthirty minutes, with solid precipitating after about five minutes ofrefluxing. The reaction mixture was cooled and the precipitate wascollected, washed with ethyl ether and dried. The solid product wasrecrystallized from methanol and dried in vacuo at 80° C. to yield 13 g.of 1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotinonitrile as its sodium salt,m.p. >300° C. Subsequent concentrations of the mother liquor yieldedadditional fractions of 10 g., 6.5 g. and 3 g. of the product, therebyresulting in a total of 32.5 g. of said sodium salt which is readilyconverted by treatment with hydrochloric acid as in Example A-2 to thecorresponding N-H compound, that is,1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotinonitrile.

An alternative method of preparing1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotinonitrile is given as follows: Amixture containing 15 g. of α-(4-pyridyl)malonaldehyde, 9.3 g. ofα-cyanoacetamide, 11 g. of morpholine, 13 g. of acetic acid and 1 literof benzene was refluxed for about twenty-four hours with a waterseparator connected to the reaction vessel, then allowed to stand overthe weekend. The solid which had separated was collected, recrystallizedfrom dimethylformamide and dried in vacuo at 90° C. for about fifteenhours to yield 5 g. of 1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotinonitrile,m.p. >300° C.

A-2. 1,2-Dihydro-2-oxo-5-(3-pyridinyl)nicotinonitrile

A mixture containing 93 g. of α-(3-pyridinyl)-β-dimethylaminoacrolein,54 g. of α-cyanoacetamide, 65 g. of sodium methoxide and 900 ml. ofmethanol was refluxed with stirring for two hours and then allowed tostand at room temperature overnight. The resulting semi-solid cake wascooled and the solid was collected, washed with isopropyl alcohol andthen ethyl ether and dried. The solid (sodium salt) was dissolved inwater, the aqueous solution neutralized with 6 N hydrochloric acid, andthe acidic solution was cooled. The separated solid was collected,washed successively with isopropyl alcohol and ether and dried in vacuoat 80° C. to yield 41 g. of1,2-dihydro-2-oxo-5-(3-pyridinyl)nicotinonitrile, m.p. >300° C.

The above intermediate α-(3-pyridinyl)-β-dimethylaminoacrolein wasprepared as follows: to 740 ml. of dimethylformamide kept below 10° C.was added dropwise with stirring 294 g. of phosphorus oxychloride andstirring was continued for another fifteen minutes then there was added88 g. of α-(3-pyridinyl)acetic acid and the resulting reaction mixturewas stirred at room temperature for one hour and then heated withstirring at about 70° C. for two hours and then cooled. The reactionmixture was then evaporated in vacuo to remove all of the volatilematerials and the residue was added slowly to 1.24 liters of saturatedpotassium carbonate solution and 500 ml. of benzene with cooling. Themixture was allowed to stand overnight and then extracted with fourportions of 50/50 (v/v) of benzene/ethanol. The combined extracts weredried over anhydrous potassium carbonate and evaporated in vacuo toremove the solvent and thereby yield 136 g. of dark oily materialcontaining α-(3-pyridinyl)-β-dimethylacrolein.

A-3. 1,2-Dihydro-2-oxo-5-(2-pyridinyl)nicotinonitrile

A mixture containing 51 g. of α-(2-pyridinyl)-β-dimethylaminoacrolein,24 g. of α-cyanoacetamide, 31 g. of sodium methoxide and 500 ml. ofmethanol was refluxed with stirring for four hours and then allowed tostand at room temperature overnight. The mixture was filtered and thefiltrate evaporated in vacuo to remove the volatile materials. Theresidue was diluted with water and the mixture neutralized with 6 Nhydrochloric acid. The separated solid was collected, washedsuccessively with water, ethanol and ether and then dried at 80° C. invacuo to yield 18 g. of1,2-dihydro-2-oxo-5-(2-pyridinyl)nicotinonitrile.

The above intermediate α-(2-pyridinyl)-β-dimethylaminoacrolein wasprepared following the procedure described in Example A-2 using 50 g. ofα-(2-pyridinyl)acetic acid hydrochloride, 336 ml. of dimethylformamideand 80 ml. of phosphorous oxychloride.

Following the procedure described in Example A-2 but using in place ofplace of α-(3-pyridinyl)-β-dimethylaminoacrolein a molar equivalentquantity of the appropriate α-PY-β-dimethylaminoacrolein, the1,2-dihydro-2-oxo-5-PY-nicotinonitrile of Examples A-4 thru A-7 areobtained. The intermediate α-PY-β-dimethylaminoacroleins used inExamples A-4 thru A-7 are prepared following the procedure described inthe second paragraph of Example A-2 to produceα-(3-pyridinyl)-β-dimethylaminoacrolein but using in place ofα-(3-pyridinyl)acetic acid a molar equivalent quantity of theappropriate α-PY-acetic acid.

A-4.

1,2-Dihydro-2-oxo-5-(2-methyl-3-pyridinyl)nicotinonitrile usingα-(2-methyl-3-pyridinyl)-β-dimethylaminoacrolein, in turn prepared fromα-(2-methyl-3-pyridinyl)acetic acid.

A-5.

1,2-Dihydro-2-oxo-5-(5-methyl-3-pyridinyl)-nicotinonitrile usingα-(5-methyl-3-pyridinyl)-β-dimethylaminoacrolein, in turn prepared fromα-(5-methyl-3-pyridinyl)-acetic acid.

A-6.

1,2-Dihydro-2-oxo-5-(3-ethyl-4-pyridinyl)-nicotinonitrile usingα-(3-ethyl-4-pyridinyl)-β-dimethylaminoacrolein, in turn prepared fromα-(3-ethyl-4-pyridinyl)-acetic acid.

A-7.

1,2-Dihydro-2-oxo-5-(4,6-dimethyl-2-pyridinyl)nicotinonitrile usingα-(4,6-dimethyl-2-pyridinyl)-β-dimethylaminoacrolein, in turn preparedfrom α-(4,6-dimethyl-2-pyridinyl)acetic acid.

B. 1,2-DIHYDRO-2-OXO-5-(PYRIDINYL)NICOTINIC ACIDS B-1.1,2-Dihydro-2-oxo-5-(4-pyridinyl)nicotinic acid

A mixture containing 227 g. of1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotinonitrile and 2.6 liters of 50%aqueous sulfuric acid was refluxed for five hours and then allowed tostand at room temperature overnight (about fifteen hours). The reactionmixture was then poured into 1 liter of water and the mixture cooled.The precipitate was collected, washed successively with water, ethanoland ether, and dried overnight in a vacuum oven at 80° C. to yield 206g. of the crude product as a pink solid. A 40 g. portion of the crudeproduct was mixed with water and the mixture neutralized by addition ofpotassium carbonate. The solid was collected, washed successively withwater, methanol, and ether, and then recrystallized fromdimethylformamide followed by successive washing with methanol andether, and then drying in vacuo at 80° C. to yield, as a white solid, 27g. of 1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotinic acid, m.p. >300° C.

B-2. 1,2-Dihydro-2-oxo-5-(3-pyridinyl)nicotinic acid

A mixture containing 41 g. of1,2-dihydro-2-oxo-5-(3-pyridinyl)nicotinonitrile and 410 ml. of 50%aqueous sulfuric acid was refluxed for two hours and then poured into1.5 kg. of a mixture of ice and water. The acidic mixture wasneutralized with 35% aqueous sodium hydroxide solution and the mixturecooled. The separated solid was collected, washed with water and driedin vacuo at 80° C. to yield 47 g. of1,2-dihydro-2-oxo-5-(3-pyridinyl)nicotinic acid which was used directlywithout further purification in the next step described below as ExampleC-2.

B-3. 1,2-Dihydro-2-oxo-5-(2-pyridinyl)nicotinic acid,

14 g., was obtained following the procedure described in Example B2using 18 g. of 1,2-dihydro-2-oxo-5-(2-pyridinyl)nicotinotrile, 180 ml.of 50% aqueous sulfuric acid and a reflux period of four hours.

Following the procedure described in Example B-2 but using in place of1,2-dihydro-2-oxo-5-(3-pyridinyl)nicotinonitrile a molar equivalentquantity of a 1,2-dihydro-2-oxo-5-PY-nicotinonitrile, the corresponding1,2-dihydro-2-oxo-5-PY-nicotinic acids of Examples B-4 thru B-7 areobtained.

B-4.

1,2-Dihydro-2-oxo-5-(2-methyl-3-pyridinyl)-nicotinic acid using1,2-dihydro-2-oxo-5-(2-methyl-3-pyridinyl)-nicotinonitrile.

B-5.

1,2-Dihydro-2-oxo-5-(5-methyl-3-pyridinyl)-nicotinic acid using1,2-dihydro-2-oxo-5-(5-methyl-3-pyridinyl)-nicotinonitrile.

B-6.

1,2-Dihydro-2-oxo-5-(3-ethyl-4-pyridinyl)-nicotinic acid using1,2-dihydro-2-oxo-5-(3-ethyl-4-pyridinyl)-nicotinonitrile.

B-7.

1,2-Dihydro-2-oxo-5-(4,6-dimethyl-2-pyridinyl)-nicotinic acid using1,2-dihydro-2-oxo-5-(4,6-dimethyl-2-pyridinyl)-nicotinonitrile.

C. 3-NITRO-5-(PYRIDINYL)-2(1H)-PYRIDINONES C-1.3-Nitro-5-(4-pyridinyl)-2(1H)-pyridinone

To a stirred solution kept at 5°-10° C. and containing 154 g. of1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotinic acid in 450 ml. ofconcentrated sulfuric acid was added dropwise a solution containing 45ml. of concentrated sulfuric acid and 160 ml. of 90% nitric acid. Thereaction mixture was heated cautiously at 80° C. for three hours andthen poured into 3.3 liters of a mixture of ice and water. The mixturewas filtered and the precipitate washed with water. The combinedfiltrates were added slowly to one liter of 10% aqueous potassiumcarbonate solution with stirring. The solution was neutralized by addingpotassium carbonate and then made alkaline by adding 5% aqueous sodiumbicarbonate solution. The precipitated product was collected, washedsuccessively with a small amount of cold water, isopropyl alcohol andether, and then dried in vacuo at 80° C. to yield 89 g. of the product.A 30 g. portion of the product was recrystallized from dimethylformamideto yield 20 g. of 3-nitro-5-(4-pyridinyl)-2(1H)-pyridinone, m.p.>300° C.

Alternatively, 3-nitro-5-(4-pyridinyl)-2(1H)-pyridinone is preparedstep-wise starting with1,2-dihydro-2-oxo-5-(4-pyridinyl)-nicotinonitrile as follows: A mixturecontaining 197 g. of 1,2-dihydro-2-oxo-5-(4-pyridinyl)-nicotinonitrile,600 ml. of concentrated sulfuric acid and 150 liters of water wasrefluxed for twenty-four hours, cooled and poured into 10 liters of amixture of ice and water. The mixture was neutralized with ammoniumhydroxide and the separated precipitate was collected, washed with asmall amount of cold water and dried in vacuo at 80° C. to yield 148 g.of 5-(4-pyridinyl)-2(1H)-pyridinone, m.p. 258°-260° C. An 80 g. portionof 5-(4-pyridinyl)-2(1H)-pyridinone was added to 288 ml. of concentratedsulfuric acid and the mixture heated to 70° C. To this stirred solutionkept at 70°-80° C. was added dropwise a mixture containing 102 ml. of90% nitric acid and 29 ml. of concentrated sulfuric acid. The reactionmixture was heated at about 80° C. for three hours after addition of themixture of acids. The reaction mixture was then cooled and poured into amixture of ice and water with stirring. The precipitate was collectedand dried. It was then slurried with water and neutralized with 10%aqueous potassium bicarbonate solution. The precipitate was collected,washed with water and dried in vacuo at 80° C. to yield 56 g. of3-nitro-5-(4-pyridinyl)-2(1H)-pyridinone.

Following the procedure described in the immediately preceding paragraphbut starting with a molar equivalent quantity of the appropriate1,2-dihydro-2-oxo-5-PY-nicotinonitrile in place of1,2-dihydro-2-oxo-5-(4-pyridinyl)-nicotinonitrile, there are obtainedfirst the following 5-PY-2(1H)-pyridinones:5-(3-pyridinyl)-2(1H)-pyridinone; 5-(2-pyridinyl)-2(1H)-pyridinone;5-(2-methyl-3-pyridinyl)-2(1H)-pyridinone;5-(5-methyl-3-pyridinyl)-2(1H)-pyridinone;5-(3-ethyl-4-pyridinyl)-2(1H)-pyridinone; and,5-(4,6-dimethyl-2-pyridinyl)-2(1H)-pyridinone. In the subsequent secondstep, that is, the treatment of the appropriate 5-PY-2(1H)-pyridinonewith concentrated sulfuric acid and concentrated nitric acid as above,there are obtained the corresponding respective 3-nitro compounds.

C-2. 3-Nitro-5-(3-pyridinyl)-2(1H)-pyridinone,

14 g., m.p.>300° C., was prepared following the procedure described inExample C-1 using 25 g. of 1,2-dihydro-2-oxo-5-(3-pyridinyl)nicotinicacid, 76.4 ml. of concentrated sulfuric acid, 26.6 ml. of 90% nitricacid and 7.6 ml. of concentrated sulfuric acid.

C-3. 3-Nitro-5-(2-pyridinyl)-2(1H)-pyridinone,

10 g., m.p.>300° C., was prepared following the procedure described inExample C-1 using 14 g. of 1,2-dihydro-2-oxo-5-(2-pyridinyl)nicotinicacid, 44 ml. of concentrated sulfuric acid, 15 ml. of 90% nitric acidand 4.4 ml. of concentrated sulfuric acid.

C-4. 1-Methyl-3-nitro-5-(4-pyridinyl)-2(1H)-pyridinone

A mixture containing 4.3 g. of 3-nitro-5-(4-pyridinyl)-2(1H)-pyridinone,2.8 g. of anhydrous potassium carbonate and 40 ml. of drydimethylformamide was stirred under nitrogen and heated on a steam bathfor thirty minutes. The resulting fine suspension was cooled to roomtemperature and to it was added dropwise with stirring 3.7 g. of methyltosylate. The resulting mixture was then stirred at room temperature foreighteen hours, at steam bath temperature for ninety minutes, cooled andthen poured onto ice. The separated solid was collected, washed wellwith water and dried at 60° C. and one-third atmosphere for eight hours.The resulting powder (3.2 g.) was crystallized from 50% aqueous ethanolto yield fine needles which were washed well with water and dried invacuo for three hours at 100° C. and 10 mm. to yield 2.2 g. of1-methyl-3-nitro-5-(4-pyridinyl)2(1H)-pyridinone, m.p. 250°-252° C. Inorder to prove that the product obtained here was the N-methyl compoundand not the O-methyl compound the following experiment was conducted: To300 mg. of the product dissolved in 10 ml. of glacial acetic acid wasadded 2 ml. of 48% hydrogen bromide and the resulting clear solution washeated on a steam bath for about seventy-five minutes, cooled and thesolvents distilled-off under reduced pressure. The residual yellow solidwas triturated with dilute aqueous ammonium hydroxide solution,collected by filtration, washed with water and dried at 80° C. andone-third atmosphere for twenty hours to yield 0.30 g. of the startingmaterial, m.p. 252°-254° C. Had the product been the O-methyl compound,that is, 2-methoxy-3-nitro-5-(4-pyridinyl)pyridine, the foregoingrefluxing with hydrogen bromide in acetic acid would have produced thedemethylated compound namely, 3-nitro-5-(4-pyridinyl)-2(1H)-pyridinone.

In another run following the above-described procedure there wasobtained 11.2 g. of 1-methyl-3-nitro-5-(4-pyridinyl)-2(1H)-pyridinone,m.p. 151°-152° C., using 21.7 g. of3-nitro-5-(4-pyridinyl)-2(1H)-pyridinone, 13.8 g. of anhydrous potassiumcarbonate, 300 ml. of dimethylformamide, 18.6 g. of methyl tosylate in50 ml. of dimethylformamide added in one portion, and recrystallizationfrom aqueous ethanol.

C-5. 1-Ethyl-3-nitro-5-(4-pyridinyl)-2(1H)-pyridinone

A mixture containing 21.7 g. of3-nitro-5-(4-pyridinyl)-2(1H)-pyridinone, 13.8 g. of anhydrous potassiumcarbonate and 400 ml. of dry dimethylformamide was stirred at roomtemperature for one hour on a steam bath for one hour and then allowedto cool to room temperature. To the stirred yellow suspension was addeda solution containing 20 g. of ethyl tosylate in 10 ml. ofdimethylformamide and the resulting mixture was stirred at roomtemperature overnight (about fifteen hours) and then on a steam bath forninety minutes. The mixture was cooled and filtered. The filtrate wasconcentrated to near dryness under reduced pressure and 400 ml. of waterwas added. The yellow solid was collected by filtration, washed withwater and dried at 50° C. in vacuo for eighteen hours to yield 5.5 g. ofpale yellow needles, m.p. 124°-126° C. (see below for recrystallizationand identification). The filtrate was stored at 0° C. and the resultingyellow crystalline precipitate was collected and dried at 100° C. and 10mm. for four hours to yield 8.0 g. of the product,1-ethyl-3-nitro-5-(4-pyridinyl)-2(1H)-pyridinone, m.p. 175°-176° C. Asample of this product was recrystallized from 95% ethanol to producethe yellow crystalline 1-ethyl compound, m.p. 175°-176° C., whosenuclear magnetic resonance spectrum (10% in CF₃ COOD) is consistent withthe assigned N-ethyl structure. A portion of the above-noted pale yellowneedles melting at 124°-126° C. was recrystallized from ethanol-water(3/1, v/v) to yield white needles, m.p. 126°-127° C., which wasidentified by its nuclear magnetic resonance spectrum (10% in CF₃ COOD)as 2-ethoxy-3-nitro-5-(4-pyridinyl)pyridine.

Following the procedure described in Example C-1 but using in place of1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotinic acid a molar equivalentquantity of the appropriate 1,2-dihydro-2-oxo-5-PY-nicotinic acid, thecorresponding 3-nitro-5-PY-2(1H)-pyridinones of Examples C-6 thru C-9are obtained.

C-6.

3-Nitro-5-(2-methyl-3-pyridinyl)-2(1H)-pyridinone using1,2-dihydro-2-oxo-5-(2-methyl-3-pyridinyl)-nicotinic acid.

C-7.

3-Nitro-5-(5-methyl-3-pyridinyl)-2(1H)-pyridinone using1,2-dihydro-2-oxo-5-(5-methyl-3-pyridinyl)-nicotinic acid.

C-8.

3-Nitro-5-(3-ethyl-4-pyridinyl)-2(1H)-pyridinone using1,2-dihydro-2-oxo-5-(3-ethyl-4-pyridinyl)-nicotinic acid.

C-9.

3-Nitro-5-(4,6-dimethyl-2-pyridinyl)-2(1H)-pyridinone using1,2-dihydro-2-oxo-5-(4,6-dimethyl-2-pyridinyl)-nicotinic acid.

Following the procedure described in Example C-5 but using in place ofethyl tosylate a molar equivalent quantity of the appropriatelower-alkyl tosylate or other lower-alkylating agents, the corresponding1-(lower-alkyl)-3-nitro-5-PY-2(1H)-pyridinones of Examples C-10, C-11,C-12 and C-13 are obtained.

C-10.

3-Nitro-1-n-propyl-5-(4-pyridinyl)-2(1H)-pyridinone using3-nitro-5-(4-pyridinyl)-2(1H)-pyridinone and n-propyl tosylate.

C-11.

1-Isobutyl-5-(2-methyl-3-pyridinyl)-3-nitro-2(1H)-pyridinone using5-(2-methyl-3-pyridinyl)-3-nitro-2(1H)-pyridinone and isobutyl tosylate.

C-12.

1-n-Hexyl-3-nitro-5-(4-pyridinyl)-2(1H)-pyridinone using3-nitro-5-(4-pyridinyl)-2(1H)-pyridinone and n-hexyl tosylate.

C-13.

1-(2-Hydroxyethyl)-3-nitro-5-(4-pyridinyl)2(1H)-pyridinone using3-nitro-5-(4-pyridinyl)-2(1H)-pyridinone and 2-hydroxyethyl tosylate.

C-14.

3-Nitro-1-n-propyl-5-(4-pyridinyl)-2(1H)-pyridinone

A suspension containing 62.5 g. of3-nitro-5-(4-pyridinyl)-2(1H)-pyridinone, 41.5 g. of anhydrous potassiumcarbonate and 1 liter of dimethylformamide was stirred and heated on asteam bath for thirty minutes. The reaction mixture was then cooled toabout 40° C. and 51.0 g. of n-propyl iodide was added in one portion andthe resulting mixture was stirred at room temperature for ninety minutesand then at 100° C. for four hours. The reaction mixture was filteredand the filtrate was concentrated to about one-third of its volume underreduced pressure. The resulting mixture was poured into 1 liter of coldwater whereupon a red viscous oil separated. The mixture was extractedwith three 150 ml. portions of chloroform and the combined extracts werewashed successively with two 150 ml. portions of water and two 150 ml.portions of saturated brine and then dried over anhydrous magnesiumsulfate, treated with decolorizing charcoal and filtered. The filtratewas distilled under reduced pressure to remove the chloroform, therebyleaving 66.5 g. of dark viscous oil. A 60 g. portion of said darkviscous oil was dissolved in 200 ml. of glacial acetic acid, 100 ml. of48 % hydrogen bromide was added, and the solution was stirred on a steambath for six hours. After distilling off most of the solvents underreduced pressure, there was added 200 ml. of water and 200 ml. ofmethylene dichloride and the mixture was made basic (pH of about 10)with 2 N potassium hydroxide solution. The layers were separated and theaqueous layer was extracted with two 100 ml. portions of methylenedichloride. The combined organic layers were shaken with brine and driedover anhydrous magnesium sulfate. The methylene dichloride was distilledoff under reduced pressure to leave 35.6 g. of pale yellow, viscous oilwhich crystallized completely on standing at room temperature. Thecrystalline product was recrystallized from boiling water and dried at80° C. and one-third atmosphere for eighteen hours to yield a first cropof 30.2 g. of 3-nitro-1-n-propyl-5-(4-pyridinyl)-2(1H)-pyridinone, m.p.139°-140° C. A second crop of 3.8 g. of product, m.p. 138°-140° C., alsowas obtained.

D. 3-AMINO-5-(PYRIDINYL)-2(1H)-PYRIDINONES (From 3-nitro compounds) D-1.3-Amino-5-(4-pyridinyl)-2(1H)-pyridinone

A mixture containing 10 g. of 3-nitro-5-(4-pyridinyl)-2(1H)pyridinone,200 ml. of dimethylformamide and 1.5 g. of 10% palladium-on-charcoal washydrogenated under pressure (50 p.s.i.) at room temperature until theuptake of hydrogen ceased (about thirty minutes). The reaction mixturewas filtered through infusorial earth and the filtrate was heated invacuo to remove the solvent. The residual material was crystallized fromdimethylformamide, washed successively with ethanol and ether, and driedin vacuum oven at 80° C. for eight hours to yield 6 g. of3-amino-5-(4-pyridinyl)-2(1H)-pyridinone, m.p. 294°-297° C. withdecomposition.

The preparations of several acid-addition salts of3-amino-5-(4-pyridinyl)-2(1H)-pyridinone are given in the followingparagraphs.

Methanesulfonate

A 20 g. portion of 3-amino-5-(4-pyridinyl)-2(1H)-pyridinone wassuspended in 250 ml. of warm methanol and methanesulfonic acid was addedin a fine stream until the pH of the mixture dropped to about 2 to 3.The mixture was chilled and the separated orange solid was collected.The crystalline solid was recrystallized twice from aqueous methanol toyield, as golden crystals, 14 g. of3-amino-5-(4-pyridinyl)-2(1H)-pyridinone methanesulfonate, m.p.280°-282° C. with decomposition, after drying in vacuo at 80° C.

Sulfate

To a solution containing 10 g. of3-amino-5-(4-pyridinyl)-2(1H)-pyridinone in about 250 ml. of aqueousmethanol was added carefully concentrated sulfuric acid until the pH ofthe solution became 3. A yellow solid formed and the mixture waschilled. The separated solid was collected, recrystallized from waterand dried at 80° C. and 0.11 mm. to yield 16.0 g. of3-amino-5-(4-pyridinyl)-2(1H)pyridinone sulfate, m.p. 287°-288° C. withdecomposition.

Phosphate

A 10 g. portion of 3-amino-5-(4-pyridinyl)-2(1H)-pyridinone wasdissolved in methanol-water and the solution made acidic by addingconcentrated phosphoric acid to a pH of 2 and the mixture was stirredwell and then allowed to stand over the weekend. The mixture waschilled; the separated solid was collected and washed successively withethanol and ether, and then dried in vacuo at 70° C. to yield 4 g. of3-amino-5-(4-pyridinyl)-2(1H)-pyridinone phosphate, m.p. 270°-272° C.with decomposition.

D-2. 3-Amino-5-(3-pyridinyl)-2(1H)-pyridinone

A mixture containing 14 g. of 3-nitro-5-(3-pyridinyl)-2(1H)-pyridinone,300 ml. of dimethylformamide and 1.75 g. of 10% palladium-on-charcoalwas hydrogenated under pressure (50 p.s.i.) at room temperature for twohours and then filtered. The solvent was distilled off in vacuo and theresidue was slurried with isopropyl alcohol. The solid was collected byfiltration and washed with ether and then dried. The solid was dissolvedin dilute aqueous hydrochloric acid; the solution was treated withdecolorizing charcoal and filtered; and, the filtrate was evaporated invacuo. The residue was slurried with isopropyl alcohol; the solidcollected by filtration, washed with ether and dried at 80° C. in vacuoto produce 11 g. of 3-amino-5-(3-pyridinyl)-2(1H)-pyridinone as itsdihydrochloride, m.p. 280°-290° C. with decomposition.

D-3. 3-Amino-5-(2-pyridinyl)-2(1H)-pyridinone

A mixture containing 10 g. of 3-nitro-5-(2-pyridinyl)-2(1H)-pyridinone,150 ml. of dimethylformamide and 1.5 g. of 10% palladium-on-charcoal washydrogenated under pressure (50 p.s.i.) at room temperature for one hourand filtered. The filter cake was washed with dimethylformamide. Thecombined filtrate and washings were evaporated in vacuo and the residualmaterial was taken up in 6 N aqueous hydrochloric acid. The acidicsolution was evaporated in vacuo and the residue was recrystallized fromdimethylformamide, washed successively with isopropyl alcohol and ether,and dried at 80° C. in vacuo to yield 2 g. of3-amino-5-(2-pyridinyl)-2(1H)-pyridinone as its monohydrochloride, m.p.259°-262° C. with decomposition.

D-4. 3-Amino-1-methyl-5-(4-pyridinyl)-2(1H)-pyridinone

A mixture containing 10.7 g. of1-methyl-3-nitro-5-(4-pyridinyl)-2(1H)-pyridinone and 200 ml. ofdimethylformamide was warmed to dissolve the nitro-pyridinone and thesolution was filtered through infusorial earth. The filtrate was chargedinto a 500 ml. Parr bottle with 1.2 g. of 10% palladium-on-charcoalcatalyst and the mixture was shaken under 40 p.s.i. of hydrogen at roomtemperature for three hours, after which time no further hydrogen wastaken up. The reaction mixture was filtered and the filtrate wasconcentrated to dryness under reduced pressure (0.1 mm.) on a water bathat 40° C. leaving 10.1 g. of brown crystalline solid. The solid wasrecrystallized three times from benzene-ethanol, the third time usingdecolorizing charcoal, to yield 4.5 g. of3-amino-1-methyl-5-(4-pyridinyl)-2(1H)-pyridinone, m.p. 175°-176° C.after drying at room temperature in vacuo for twenty hours.

D-5. 3-Amino-1-ethyl-5-(4-pyridinyl)-2(1H)-pyridinone

A solution containing 8.3 g. of1-ethyl-3-nitro-5-(4-pyridinyl)-2(1H)-pyridinone in 200 ml. of ethylacetate and 50 ml. of 95% ethanol was charged into a 500 ml. Parr bottlewith 1.8 g. of 10% palladium-on-charcoal and the mixture was shakenunder 42 p.s.i. of hydrogen at room temperature for fifty minutes afterwhich time no further hydrogen was taken up. The catalyst was filteredoff and the solution was evaporated in vacuo to leave 7.5 g. of whitecrystalline solid. The solid was recrystallized from benzene to produce,as white needles, 5.8 g. of3-amino-1-ethyl-5-(4-pyridinyl)-2(1H)-pyridinone, m.p. 181°-182° C.after drying at room temperature in vacuo for fifty hours and at 55° C.and 0.001 mm. for five hours.

Following the procedure described in Example D-4 but using in place of1-methyl-3-nitro-5-(4-pyridinyl)-2(1H)-pyridinone a molar equivalentquantity of the appropriate 1-R-3-nitro-5-PY-2(1H)-pyridinone, the1-R-3-amino-5-PY-2(1H)-pyridinones of Examples D-6 thru D-13 areobtained.

D-6.

3-Amino-1-n-propyl-5-(4-pyridinyl)-2(1H)-pyridinone using1-n-propyl-3-nitro-5-(4-pyridinyl)-2(1H)-pyridinone.

D-7.

3-Amino-1-isobutyl-5-(4-pyridinyl)-2(1H)-pyridinone using1-isobutyl-3-nitro-5-(4-pyridinyl)-2(1H)-pyridinone.

D-8.

3-Amino-1-n-hexyl-5-(4-pyridinyl)-2(1H)-pyridinone using1-n-hexyl-3-nitro-5-(4-pyridinyl)-2(1H)-pyridinone.

D-9.

3-Amino-5-(2-methyl-3-pyridinyl)-2(1H)-pyridinone using3-nitro-5-(2-methyl-3-pyridinyl)-2(1H)-pyridinone.

D-10.

3-Amino-5-(5-methyl-3-pyridinyl)-2(1H)-pyridinone using3-nitro-5-(5-methyl-3-pyridinyl)-2(1H)-pyridinone.

D-11.

3-Amino-5-(3-ethyl-4-pyridinyl)-2(1H)-pyridinone using3-nitro-5-(3-ethyl-4-pyridinyl)-2(1H)-pyridinone.

D-12.

3-Amino-5-(4,6-dimethyl-2-pyridinyl)-2(1H)-pyridinone using3-nitro-5-(4,6-dimethyl-2-pyridinyl)-2(1H)-pyridinone.

D-13.

3-Amino-1-(2-hydroxyethyl)-5-(4-pyridinyl)-2(1H)-pyridinone using1-(2-hydroxyethyl)-3-nitro-5-(4-pyridinyl)-2(1H)-pyridinone.

D-14. 3-Amino-1-n-propyl-5-(4-pyridinyl)-2(1H)-pyridinone

A solution containing 15.1 g. of3-nitro-1-n-propyl-5-(4-pyridinyl)-2(1H)-pyridinone in 400 ml. of drydimethylformamide was charged into an 800 ml. Parr bottle with 1.5teaspoons of Raney nickel and the mixture was shaken under 650 p.s.i ofhydrogen at room temperature for four hours, during which time thereaction temperature was no more than 50° C. The catalyst was filteredoff; the filtrate was treated with decolorizing charcoal and filtered;and, the solvent was distilled off under reduced pressure to leave 12.7g. of crystalline solid. The solid was recrystallized from methanol toyield 7.2 g. of crystalline3-amino-1-n-propyl-5-(4-pyridinyl)-2(1H)-pyridinone, m.p. 171°-173° C.after drying at 70° C. and 0.001 mm. for six hours.

E. 1,2-DIHYDRO-2-OXO-5-(PYRIDINYL)NICOTINAMIDES E-1.1,2-Dihydro-2-oxo-5-(4-pyridinyl)nicotinamide (optionally named1,6-dihydro-6-oxo[3,4'-bipyridin]-5-carboxamide)

A mixture containing 10 g. of1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotinonitrile and 100 ml. of 90%sulfuric acid was heated on a steam bath for one hour and then pouredinto ice. The acidic solution was neutralized with 35% aqueous sodiumhydroxide solution and then made basic with 10% potassium bicarbonatesolution. The separated product was collected, washed with water, dried,recrystallized from dimethylformamide, washed successively with ethanoland ethyl ether, and dried in vacuo at 80° C. to yield 8.5 g. of1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotinamide, m.p. >300° C.

In another run using 68 g. of1,2-dihydro-2-oxo-4-(4-pyridinyl)nicotinonitrile, 700 ml. of 90%sulfuric acid, a heating period of two hours on a steam bath, isolationas above, recrystallization from dimethylformamide and washing withmethanol and ether followed by drying, there was obtained a quantativeyield, 80 g. of the product,1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotinamide, m.p. 300° C.

E-2. 1,2-Dihydro-5-(4-pyridinyl)nicotinamide

A reaction mixture containing 17.6 g. ofα-(4-pyridinyl)-β-dimethylaminoacrolein, 10.0 g. of malonamide, 10.8 g.of sodium methoxide and 200 ml. of methanol was refluxed for thirtyminutes and allowed to cool. The separated product was collected anddried to yield "A". The mother liquor was concentrated in vacuo toremove the solvent and the residual material was diluted with water. Themixture was neutralized with acetic and the solid was collected, washedwith water and dried to yield "B". "A" was dissolved in water and thesolution was neutralized with acetic acid and the mixture cooled. Theseparated solid was collected, washed with water and dried. "A" and "B"were combined and recrystallized from 400 ml. of dimethylformamide toyield 13 g. of 1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotinamide, m.p. >300°C. The product obtained by this procedure was identical with thecompound obtained in the immediately preceding Example E-1.

Following the procedure described in Example E-1 but using in place of1,2-dihydro-2-oxo-5-(4-pyridinyl)-nicotinonitrile a molar equivalentquantity of the appropriate 1,2-dihydro-2-oxo-5-PY-nicotinonitrile, the1,2-dihydro-2-oxo-5-PY-nicotinamides of Examples E-3 thru E-8 areobtained.

E-3.

1,2-Dihydro-2-oxo-5-(3-pyridinyl)nicotinamide using1,2-dihydro-2-oxo-5-(3-pyridinyl)nicotinonitrile.

E-4.

1,2-Dihydro-2-oxo-5-(2-pyridinyl)nicotinamide using1,2-dihydro-2-oxo-5-(2-pyridinyl)nicotinonitrile.

E-5.

1,2-Dihydro-2-oxo-5-(2-methyl-3-pyridinyl)-nicotinamide using1,2-dihydro-2-oxo-5-(2-methyl-3-pyridinyl)-nicotinonitrile.

E-6.

1,2-Dihydro-2-oxo-5-(5-methyl-3-pyridinyl)-nicotinamide using1,2-dihydro-2-oxo-5-(5-methyl-3-pyridinyl)-nicotinonitrile.

E-7.

1,2-Dihydro-2-oxo-5-(3-ethyl-4-pyridinyl)-nicotinamide using1,2-dihydro-2-oxo-5-(3-ethyl-4-pyridinyl)-nicotinonitrile.

E-8.

1,2-Dihydro-2-oxo-5-(4,6-dimethyl-2-pyridinyl)-nicotinamide using1,2-dihydro-2-oxo-5-(4,6-dimethyl-2-pyridinyl)-nicotinonitrile.

The products of E-3 thru E-8 also are produced by following theprocedure described in Example E-2 using in place ofα-(4-pyridinyl)-β-dimethylacrolein a molar equivalent quantity of theappropriate α-PY-β-dimethylacrolein, e.g.,1,2-dihydro-2-oxo-5-(3-pyridinyl)nicotinamide usingα-(3-pyridinyl)-β-dimethylaminoacrolein, and the like.

F. 3-AMINO-5-(PYRIDINYL)-2(1H)-PYRIDINONES (From 3-CONH₂ compounds) F-1.3-Amino-5-(4-pyridinyl)-2(1H)-pyridinone

To a solution containing 90 g. of sodium hydroxide in 1300 ml. of waterkept at 0° C. was added dropwise with stirring 23 ml. of bromine. To thereaction mixture was then added 80 g. of1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotinamide and the resulting reactionmixture was heated on a steam bath for three hours. The reaction mixturewas cooled to room temperature, acidified slowly with 6 N hydrochloricacid and the resulting acidic mixture was stirred for an additionalthirty minutes. The acidic mixture was neutralized with 10% aqueouspotassium bicarbonate solution and the mixture cooled. The precipitatewas collected, washed with water and dried. The solid product wasrecrystallized from dimethylformamide, washed successively with methanoland ethyl ether and dried in vacuo at 80° C. to yield 35 g. of3-amino-5-(4-pyridinyl)-2(1H)-pyridinone, m.p. 295°-297° C. withdecomposition. Another 7 g. of the product was obtained by diluting themother liquor with ethyl ether.

Following the procedure described in Example F-1 but using in place of1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotinamide a molar equivalentquantity of the appropriate 1,2-dihydro-2-oxo-5-PY-nicotinamide, the3-amino-5-PY-2(1H)-pyridinones of Examples F-2 thru F-7 are obtained.

F-2.

3-Amino-5-(3-pyridinyl)-2(1H)-pyridinone using1,2-dihydro-2-oxo-5-(3-pyridinyl)nicotinamide.

F-3.

3-Amino-5-(2-pyridinyl)-2(1H)-pyridinone using1,2-dihydro-2-oxo-5-(2-pyridinyl)nicotinamide.

F-4.

3-Amino-5-(2-methyl-3-pyridinyl)-2(1H)-pyridinone using1,2-dihydro-2-oxo-5-(2-methyl-3-pyridinyl)nicotinamide.

F-5.

3-Amino-5-(5-methyl-3-pyridinyl)-2(1H)-pyridinone using1,2-dihydro-2-oxo-5-(5-methyl-3-pyridinyl)nicotinamide.

F-6.

3-Amino-5-(3-ethyl-4-pyridinyl)-2(1H)-pyridinone using1,2-dihydro-2-oxo-5-(3-ethyl-4-pyridinyl)nicotinamide.

F-7.

3-Amino-5-(4,6-dimethyl-2-pyridinyl)-2(1H)-pyridinone using1,2-dihydro-2-oxo-5-(4,6-dimethyl-2-pyridinyl)nicotinamide.

G. 1,2-DIHYDRO-3-(ACYLAMIDO)-5-(PYRIDINYL)-2(1H)-PYRIDINONES G-1.N-[1,2-Dihydro-2-oxo-5-(4-pyridinyl)-3-pyridinyl]acetamide

A mixture containing 9.4 g. of 3-amino-5-(4-pyridinyl)-2(1H)-pyridinone,5.6 g. of acetic anhydride and 120 ml. of pyridine was heated on a steambath for one hour and then allowed to cool. The separated product wascollected, washed with ether and dried, and recrystallized twice fromdimethylformamide to yield 8 g. ofN-[1,2-dihydro-2-oxo-5-(4-pyridinyl)-3-pyridinyl]acetamide, m.p. >300°C.

G-2. Methyl N-[1,2-dihydro-2-oxo-5-(4-pyridinyl)-3-pyridinyl]carbamate

A mixture containing 10 g. of 3-amino-5-(4-pyridinyl)-2(1H)-pyridinone,100 ml. of dimethylformamide and 24 g. of 1,1'-carbonyldiimidazole wasstirred at room temperature for two hours and the solvent then distilledoff in vacuo. Cold water was added to the residue and the mixture wasstirred until the evolution of carbon dioxide stopped. The solid wascollected, washed with water and dried. The solid was next slurried withacetone, collected and dried. The solid was dissolved in 200 ml. ofdimethylformamide, the solution treated with decolorizing charcoal andthe mixture filtered. The filtrate was heated in vacuo to remove thedimethylformamide. The remaining material, which consisted primarily ofN-[1,2-dihydro-2-oxo-5-(4-pyridinyl)-3-pyridinyl]-imidazole-1-carboxamide,was heated with methanol whereupon a reaction ensued. The reactionmixture was allowed to cool and the separated product was collected anddried to yield 3.5 g. of methylN-[1,2-dihydro-2-oxo-5-(4-pyridinyl)-3-pyridinyl]carbamate, m.p. >300°C.

Following the procedure described in Example G-1 but using in place ofacetic anhydride a molar equivalent quantity of the appropriateacylating agent, the compounds of Examples G-3 thru G-5 are obtained.

G-3.

N-[1,2-Dihydro-2-oxo-5-(4-pyridinyl)-3-pyridinyl]propionamide usingpropionic anhydride.

G-4.

N-[1,2-Dihydro-2-oxo-5-(4-pyridinyl)-3-pyridinyl]isobutyramide usingisobutyric anhydride.

G-5.

N-[1,2-Dihydro-2-oxo-5-(4-pyridinyl)-3-pyridinyl]caproamide usingcaproic anhydride.

Following the procedure described in Example G-2 but first using inplace of 3-amino-5-(4-pyridinyl)-2(1H)-pyridinone a corresponding molarequivalent quantity of the appropriate 3-amino-5-PY-2(1H)-pyridinone toproduce the correspondingN-(1,2-dihydro-2-oxo-5-PY-3-pyridinyl)-imidazole-1-carboxamide and thenreacting said imidazole-1-carboxamide with the appropriate alkanol inplace of methanol, there are obtained the corresponding lower-alkylN-(1,2-dihydro-2-oxo-5-PY-3-pyridinyl)carbamates of Examples G-6 thruG-8.

G-6.

Ethyl N-[1,2-dihydro-2-oxo-5-(4-pyridinyl)-3-pyridinyl]carbamate firstusing 3-amino-5-(4-pyridinyl)-2(1H)-pyridinone and then using ethanol.

G-7.

n-Hexyl N-[1,2-dihydro-2-oxo-5-(4-pyridinyl)-3-pyridinyl]carbamate using3-amino-5-(4-pyridinyl)-2(1H)-pyridinone and then reacting the resultingN-[1,2-dihydro-2-oxo-5-(4-pyridinyl)-3-pyridinyl]-imidazole-1-carboxamidewith n-hexanol.

G-8.

Isobutyl N-[1,2-dihydro-2-oxo-5-(4-pyridinyl)-3-pyridinyl]carbamatefirst using 3-amino-5-(4-pyridinyl)-2(1H)-pyridinone and then reactingthe resultingN-[1,2-dihydro-2-oxo-5-(4-pyridinyl)-3-pyridinyl]-1-imidazole-1-carboxamidewith isobutyl alcohol.

G-9. N-[1,2-Dihydro-2-oxo-5-(4-pyridinyl)-3-pyridinyl]formamide

(also named N-(1,6-dihydro-6-oxo-[3,4'-bipyridine]-5-yl)formamide)

A reaction mixture containing 28 g. of3-amino-5-(4-pyridinyl)-2(1H)-pyridinone and 200 ml. of 97% formic acidwas heated on a steam bath for three hours, cooled and the excess formicacid distilled-off under reduced pressure. The residue was dissolved inwater and the aqueous solution was made alkaline with ammoniumhydroxide. The precipitated product was collected, washed with water,dried, recrystallized from dimethylformamide, washed with ether anddried to yield 26 g. ofN-[1,2-dihydro-2-oxo-5-(4-pyridinyl)-3-pyridinyl]formamide, m.p.299°-300° C. with decomposition.

H. 3-HALO-5-(PYRIDINYL)-2(1H)-PYRIDINONES H-1.3-Bromo-5-(4-pyridinyl)-2(1H)-pyridinone (also named5-bromo-[3,4'-bipyridin]-6(1H)-one)

A mixture containing 51.6 g. of 5-(4-pyridinyl)-2(1H)-pyridinone and 600ml. of acetic acid was heated to about 60° C. to effect completesolution. The heat was removed and 52.8 g. of bromine was added dropwiseover a period of about twenty minutes whereupon a solid separated duringthe addition. The mixture was stirred at room temperature for aboutthirty minutes, diluted with ether and the mixture then chilled in ice.The solid was collected, washed with ether, dried, slurried with waterand neutralized with 10% potassium bicarbonate solution. The solid wascollected, washed with water and dried. The solid was then dissolved indilute hydrochloric acid and isopropyl alcohol was added to the solutionto precipitate the hydrochloride salt which was recrystallized fromwater and dried to yield 55 g. of3-bromo-5-(4-pyridinyl)-2(1H)-pyridinone as its hydrochloride,m.p. >300° C.

H-2. 3-Chloro-5-(4-pyridinyl)-2(1H)-pyridinone (also named5-chloro-[3,4'-bipyridin]-6(1H)-one)

A mixture containing 17 g. of 5-(4-pyridinyl)-2(1H)-pyridinone and 200ml. of acetic acid heated on a steam bath was treated by bubblingchlorine into it for four hours. After allowing the reaction mixture tocool to room temperature, the solid was collected, washed with ether anddried. The solid was dissolved in water and the aqueous solution wasneutralized with 2 N aqueous potassium hydroxide solution and themixture cooled. The separated solid was collected, washed with water,dried, and recrystallized from ethanol to yield 6.5 g. of3-chloro-5-(4-pyridinyl)-2(1H)-pyridinone, m.p. 295°-297° C.

H-3.

3-Chloro-5-(3-pyridinyl)-2(1H)-pyridinone is obtained following theprocedure described in Example H-2 but using a molar equivalent quantityof 5-(3-pyridinyl)-2(1H)-4-pyridinone in place of5-(4-pyridinyl)-2(1H)-pyridinone.

H-4.

3-Chloro-5-(3-ethyl-4-pyridinyl)-2(1H)-pyridinone is obtained followingthe procedure described in Example H-2 using a molar equivalent quantityof 5-(3-ethyl-4-pyridinyl)-2(1H)-pyridinone in place of5-(4-pyridinyl)-2(1H)-pyridinone.

H-5.

3-Bromo-5-(5-methyl-3-pyridinyl)-2(1H)-pyridinone is obtained followingthe procedure described in Example H-1 using5-(5-methyl-3-pyridinyl)-2(1H)-pyridinone in place of5-(4-pyridinyl)-2(1H)-pyridinone.

I. 3-(LOWER-ALKYLAMINO)-AND 3-[DI-(LOWER-ALKYL)AMINO]-5-(PYRIDINYL)-2(1H)-PYRIDINONES I-1.

3-Methylamino-5-(4-pyridinyl)-2(1H)-pyridinone (also named5-methylamino-[3,4'-bipyridin]-6-(1H)one)

A mixture containing 55 g. of 3-bromo-5-(4-pyridinyl)-2(1H)-pyridinone,200 ml. of 40% aqueous monomethylamine and 500 ml. of water wasautoclaved at 140° C. for one hundred and twenty hours. After allowingthe reaction mixture to cool to room temperature, the solid wascollected, washed with water, dried, recrystallized fromdimethylformamide, washed successively with methanol and ether, anddried to yield 10 g. of 3-methylamino-5-(4-pyridinyl)-2(1H)-pyridinone,m.p. 296°-299° C. with decomposition. Another 8 g. of product wasobtained by stripping under reduced pressure the aqueous filtrate fromthe reaction mixture, slurrying the remaining residue with a smallamount of water, collecting the solid and recrystallizing it fromdimethylformamide.

I-2. 3-Dimethylamino-5-(4-pyridinyl)-2(1H)-pyridinone (also named5-(dimethylamino)-[3,4-bipyridin]-6-(1H)-one)

A mixture contaning 36 g. of 3-amino-5-(4-pyridinyl)-2(1H)-pyridinone,40 g. of 30% aqueous formaldehyde solution and 400 ml. of formic acidwas refluxed for two and one-half hours and cooled. The reaction mixturewas heated in vacuo to remove the excess formaldehyde and formic acidand the remaining material was neutralized with 10% potassiumbicarbonate solution and allowed to stand at room temperature over theweekend. The aqueous mixture was extracted with three 150 ml. portionsof methylene dichloride and the combined extracts were dried overanhydrous magnesium sulfate and treated with decolorizing charcoal,filtered and the filtrate heated in vacuo to remove the methylenedichloride. The residue was recrystallized twice from acetonitrile,washed with ether and dried in a vacuum oven at 80° C. to yield 11.5 g.of 3-dimethylamino-5-(4-pyridinyl)-2(1H)-pyridinone, m.p. 190°-194° C.

Following the procedure described in Example I-1 but in place of3-bromo-5-(4-pyridinyl)-2(1H)-pyridinone and/or monomethylaminerespective molar equivalent quantities of the appropriate3-halo-5-(pyridinyl)-2(1H)-pyridinone and/or lower-alkylamine ordi-(lower-alkyl)amine, the compounds of Examples I-3 thru I-7 areobtained:

I-3.

3-Ethylamino-5-(3-pyridinyl)-2(1H)-pyridinone using3-chloro-5-(3-pyridinyl)-2(1H)-pyridinone and monoethylamine.

I-4.

3-Diethylamino-5-(4-pyridinyl)-2(1H)-pyridinone using3-bromo-5-(4-pyridinyl)-2(1H)-pyridinone and diethylamine.

I-5.

3-n-Propylamino-5-(3-ethyl-4-pyridinyl)-2(1H)-pyridinone using3-chloro-5-(3-ethyl-4-pyridinyl)-2(1H)-pyridinone and n-propylamine.

I-6.

3-(Diisopropylamino)-5-(5-methyl-3-pyridinyl)-2(1H)-pyridinone using3-bromo-5-(5-methyl-3-pyridinyl)-2(1H)-pyridinone and diisopropylamine.

I-7.

3-n-Hexylamino-5-(4-pyridinyl)-2(1H)-pyridinone using3-bromo-5-(4-pyridinyl)-2(1H)-pyridinone and mono-n-hexylamine.

J. DI-(LOWER-ALKYL)N-[1,2-DIHYDRO-2-OXO-5-(PYRIDINYL)-3-PYRIDINYL]AMINOMETHYLENEMALONATEJ-1. DiethylN-[1,2-dihydro-2-oxo-5-(4-pyridinyl)-3-pyridinyl]aminomethylenemalonate(also named diethyl[1,6-dihydro-6-oxo-(3,4'-bipyridin)-5-ylaminomethylene]propanedioate)

A mixture containing 9.4 g. of 3-amino-5-(4-pyridinyl)-2(1H)-pyridinone,10.8 g. of diethyl ethoxymethylenemalonate and 100 ml. of ethanol wasrefluxed with stirring on a steam bath for six and one-half hours. Thereaction mixture was filtered through infusorial earth and the filtratewas distilled in vacuo to remove the solvent. The solid residue wasrecrystallized once from ethanol and then once from methanol usingdecolorizing charcoal, washed successively with isopropyl alcohol andether, and then dried to yield 22 g. of diethylN-[1,2-dihydro-2-oxo-5-(4-pyridinyl)-3-pyridinyl]aminomethylenemalonate,m.p. 218°-222° C.

Following the procedure described in Example J-1 but using in place ofdiethyl ethoxymethylenemalonate a molar equivalent quantity of theappropriate di-(loweralkyl) (lower-alkoxy)methylenemalonate and/or usingin place of 3-amino-5-(4-pyridinyl)-2(1H)-pyridinone a molar equivalentquantity of the appropriate 3-amino-5-(pyridinyl)-2(1H)-pyridinone, thecompounds of Examples J-2 thru J-6 are obtained:

J-2.

DimethylN-[1,2-dihydro-2-oxo-5-(2-methyl-4-pyridinyl)-3-pyridinyl]aminomethylenemalonateusing dimethyl methoxymethylenemalonate and3-amino-5-(2-methyl-4-pyridinyl)-2(1H)-pyridinone.

J-3.

DiethylN-[1,2-dihydro-2-oxo-5-(3-pyridinyl)-3-pyridinyl]aminomethylenemalonateusing diethyl ethoxymethylenemalonate and3-amino-5-(3-pyridinyl)-2(1H)-pyridinone.

J-4.

DiisopropylN-[1,2-dihydro-2-oxo-5-(5-methyl-3-pyridinyl)-3-pyridinyl]aminomethylenemalonateusing diisopropyl isopropoxymethylenemalonate and3-amino-5-(5-methyl-3-pyridinyl)-2(1H)-pyridinone.

J-5.

Di-n-butylN-[1,2-dihydro-2-oxo-5-(2-methyl-4-pyridinyl)-3-pyridinyl]aminomethylenemalonateusing di-n-butyl n-butoxymethylenemalonate and3-amino-5-(2-methyl-4-pyridinyl)-2(1H)-pyridinone.

J-6.

Di-n-hexylN-[1,2-dihydro-2-oxo-5-(2,6-dimethyl-4-pyridinyl)-3-pyridinyl]aminomethylenemalonateusing di-n-hexyl n-hexoxymethylenemalonate and3-amino-5-(2,6-dimethyl-4-pyridinyl)-2(1H)-pyridinone.

The usefulness of the compounds of formula I where Q is amino(preferred), lower-alkylamino, di-(lower-alkyl)-amino, NHAc, hydrogen orcyano and the compounds of formula V as cardiotonic agents isdemonstrated by their effectiveness in standard pharmacological testprocedures, for example, in causing a significant increase in thecontractile force of the isolated cat atria and papillary muscle and incausing a significant increase in the cardiac contractile force in theanesthetized dog with low or minimal changes in heart rate and bloodpressure. These test procedures are described in the followingparagraphs.

Isolated Cat Atria and Papillary Muscle Procedure

Cats of both sexes, weighing 1.5 to 3.5 kg. are each anesthetized with30 mg./kg. i.p. of sodium pentobarbital and exsanguinated. The chest ofeach cat is opened, the heart excised, rinsed with saline, and the twoatria and one or more small, thin papillary muscles from the rightventricle are dissected. The tissues are then transferred to a Petridish filled with cold modified Tyrode's solution and bubbled with O₂. Asilver wire is attached to each of two opposite ends of the tissue andone of the wires is hooked to a glass electrode. The preparation is thenimmediately mounted in a 40 or 50 ml. organ bath filled with modifiedTyrode's solution at 37° C. The second wire is attached to aforce-displacement transducer and the tension is adjusted to obtain amaximum contractile force (papillary muscle 1.5±0.5 g., left atria3.0±0.6 g. right atria 4.5±0.8 g.). The transducer is connected to aGrass polygraph and the force and rate of contraction is recordedcontinuously. The right atrium is beating spontaneously due to thepresence of the sino-atrial node, while the left atrium and thepapillary muscle are stimulated electrically at a rate of 2 beats/sec.by a suprathreshold rectangular pulse of 0.5 millisecond duration.

The modified Tyrode's solution bathing the preparation is of thefollowing composition (in millimoles): NaCl 136.87, KCl 5.36, NaH₂ PO₄0.41. CaCl₂ 1.8, MgCl₂.6H₂ O 1.05, NaHCO₃ 11.9, glucose 5.55 and EDTA0.04. The solution is equilibrated with a gas mixture consisting of 95%O₂ and 5% CO₂ and the pH is adjusted to 7.4 with dilute solution ofsodium bicarbonate.

The preparation is left to equilibrate for one hour before any compoundis administered, and the bathing fluid is changed 3 to 4 times duringthe equilibration time. The compound dissolved in a vehicle (e.g.,Tyrode's solution or aqueous solution of acid-addition salt of compoundtested) or the vehicle alone is added to the tissue bath and the fullresponse is recorded. The tissues are washed between doses untilpre-drug control values of rate and force of contraction are obtained.Four to six doses are given to the same preparation over a period of 4to 6 hours.

When tested by the above-described Isolated Cat Atria and PapillaryMuscle Procedure, the compounds of formula I where Q is amino, NHAc,lower-alkylamino, di-(lower-alkyl)amino, NHAc, hydrogen or cyano and thecompounds of formula V, when tested at doses of 3 to 100 μg./ml., werefound to cause significant increase, that is, greater than 25%, inpapillary muscle force and a significant increase, that is, greater than25%, in right atrial force, while causing only a low percentage increase(about one-third or less than the percentage increase in right atrial orpapillary muscle force) in right atrial rate.

Anesthetized Dog Procedure

Mongrel dogs of both sexes weighing 9-15 kg. are used in this procedure.The dogs are each anesthetized with 30 mg./kg. i.v. sodiumpentobarbital. Supplemental doses of pentobarbital are administeredwhenever necessary. An intra-tracheal cannula is inserted andventilation is carried out by means of a Harvard constant-volumne,positive pressure pump using room air. The right femoral artery iscannulated and the cannula is attached to a Statham P23A pressuretransducer for the measurement of arterial blood pressure. The rightfemoral vein is cannulated and used for intravenous administration ofcompounds to be tested. Pin electrodes are attached to the rightforelimb, right hindlimb and left hindlimb, and lead IIelectrocardiogram is monitored.

A ventro-dorsal incision at the third inter-costal space is made, theheart is exposed and a Walton-Brodie strain guage is sutured to the wallof the right ventricle for the measurement of cardiac contractile force,that is, cardiac contractility. Aortic and coronary blood flow aremeasured with a pulsed field electromagnetic flow probe (CarolinaMedical Electronics) inserted around the blood vessel in question.Aortic blood flow is used as an approximate index of cardiac output andtotal peripheral resistence is calculated from aortic flow and meanarterial pressure. All the above parameters measured are recordedsimultaneously on a multi-channel Grass polygraph.

A given compound is infused into the femoral vein at a rate of from 0.03to 0.10 mg./kg./minute until a maximum inotropic effect is obtained. Theinfusion of the compound is then continued for ten more minutes tomaintain an equilibrium at this maximal inotropic effect. At the end ofthe equilibrium time the infusion is stopped and the rate of decline incardiac contractile force is observed. Alternatively, the compound isadministered intravenously as a single bolus injection of 0.30 to 30mg./kg.

When tested by the above-described Anesthetized Dog Procedure, thecompounds of formula I where Q is amino (preferred), lower-alkylamino,di-(lower-alkyl)amino, NHAc, hydrogen or cyano and the compounds offormula V, when administered intravenously at a rate of about 0.03 to0.10 mg./kg./min. or as a single bolus injection of 0.30 to 30 mg./kg.caused a significant increase, that is, greater than 25%, in cardiaccontractile force or cardiac contractility with only low or minimalchanges (less than 25%) in heart rate and blood pressure.

The actual determination of the numerical cardiotonic data definitivefor a particular compound of the invention is readily obtained accordingto the above-described standard test procedures by technicians versed inpharmacological test procedures, without any need for any extensiveexperimentation.

Preferred embodiments are subjected to further standard test procedures.For example, 3-amino-5-(4-pyridinyl)-2(1H)-pyridinone, a particularlypreferred embodiment, when tested orally in the unanesthetized dog at adose of 1.9, 3.8, 7.5 or 10 mg./kg. was found to cause, respectively, a39, 44, 47 or 98% increase in cardiac contractile force with a durationof action of more than three hours; no significant changes in bloodpressure were observed with these doses and a significant increase inheart rate was observed only at the highest dose of 10 mg./kg. p.o.

The present invention includes within its scope a cardiotoniccomposition for increasing cardiac contractility, said compositioncomprising a pharmaceutically-acceptable carrier and, as the activecomponent thereof, a cardiotonic 1-R-3-Q-5-PY-2(1H)-pyridinone offormula I where Q is amino (preferred), lower-alkylamino,di-(lower-alkyl)amino, NHAc, hydrogen or cyano, or a cardiotonicdi-(lower-alkyl)N-[1,2-dihydro-2-oxo-5-(pyridinyl)-3-pyridinyl]aminomethylenemalonate offormula V, or pharmaceutically-acceptable acid-addition salt thereof.The invention also includes within its scope the method for increasingcardiac contractility in a patient requiring such treatment whichcomprises administering to such patient an effective amount of said1-R-3-Q-5-PY-2(1H)-pyridinone of formula I where Q is amino (preferred),loweralkylamino, di-(lower-alkyl)amino, NHAc, hydrogen or cyano, or acardiotonic di-(lower-alkyl)N-[1,2-dihydro-2-oxo-5-(pyridinyl)-3-pyridinyl]aminomethylenemalonate offormula V, or pharmaceutically-acceptable acid-addition salt thereof. Inclinical practice the said compounds of formula I or V will normally beadministered orally or parenterally in a wide variety of dosage forms.

Solid compositions for oral administration include compressed tablets,pills, powders and granules. In such solid compositions, at least one ofthe active compounds is admixed with at least one inert diluent such asstarch, calcium carbonate, sucrose or lactose. These compositions mayalso contain additional substances other than inert diluents, e.g.,lubricating agents, such as magnesium stearate talc and the like.

Liquid compositions for oral administration includepharmaceutically-acceptable emulsions, solutions, suspensions, syrupsand elixirs containing inert diluents commonly used in the art, such aswater and liquid paraffin. Besides inert diluents such compositions mayalso contain adjuvants, such as wetting and suspending agents, andsweetening, flavouring, perfuming and preserving agents. According tothe invention, the compounds for oral administration also includecapsules of absorbable material, such as gelatin, containing said activecomponent with or without the addition of diluents or excipients.

Preparations according to the invention for parenteral administrationinclude sterile aqueous, aqueous-organic, and organic solutions,suspensions and emulsions. Examples of organic solvents or suspendingmedia are propylene glycol, polyethylene glycol, vegetable oils such asolive oil and injectable organic esters such as ethyl oleate. Thesecompositions may also contain adjuvants such as stabilising, preserving,wetting, emulsifying and dispersing agents.

They may be sterilized, for example by filtration through abacteria-retaining filter, by incorporation of sterilising agents in thecompositions, by irradiation or by heating. They may also bemanufactured in the form of sterile solid compositions which can bedissolved in sterile water or some other sterile injectable mediumimmediately before use.

The percentage of active component in the said composition and methodfor increasing cardiac contractility may be varied so that a suitabledosage is obtained. The dosage administered to a particular patient isvariable, depending upon the clinician's judgement using as thecriteria: the route of administration, the duration of treatment, thesize and condition of the patient, the potency of the active componentand the patient's response thereto. An effective dosage amount of activecomponent can thus only be determined by the clinician considering allcriteria and utilizing his best judgement on the patient's behalf.

We claim:
 1. The process for preparing a 3-Q-5-PY-2(1H)pyridinone havingthe formula ##STR4## where PY is 4- or 3- or 2-pyridinyl or 4- or 3- or2-pyridinyl having one or two lower-alkyl substituents, and Q iscarbamyl or amino, which comprises reacting α-PY-β-(R₁ R₂ N)acroleinwith malonamide to produce 1,2-dihydro-2-oxo-5-PY-nicotinamide andreacting 1,2-dihydro-2-oxo-5-PY-nicotinamide with an alkali metalhypohalite to produce 3-amino-5-PY-2(1H)-pyridinone, where R₁ and R₂ areeach lower-alkyl.
 2. The process according to claim 1 where PY is4-pyridinyl and the second step conversion of carbamyl to amino iscarried out using bromine and an alkali hydroxide.
 3. The process whichcomprises reacting α-PY-β-(R₁ R₂ N)acrolein with malonamide to produce1,2-dihydro-2-oxo-5-PY-nicotinamide having the formula ##STR5## where PYis 4- or 3- or 2-pyridinyl or 4- or 3- or 2-pyridinyl having one or twolower-alkyl substituents, and R₁ and R₂ are each lower-alkyl.
 4. Theprocess according to claim 3 where PY is 4-pyridinyl.
 5. The processwhich comprises reacting 1,2-dihydro-2-oxo-5-PY-nicotinamide having theformula ##STR6## where PY is 4- or 3- or 2-pyridinyl or 4- or 3- or2-pyridinyl having one or two lower-alkyl substituents, with an alkalimetal hypohalite to produce the corresponding3-amino-5-PY-2-2(1H)-pyridinone.
 6. The process according to claim 5where PY is 4-pyridinyl and the conversion of carbamyl to amino iscarried out using bromine and an alkali hydroxide.
 7. The process whichcomprises reacting either α-PY-β-(R₁ R₂ N)acrolein or α-PY-malonaldehydewith α-cyanoacetamide to produce 1,2-dihydro-2-oxo-5-PY-nicotinonitrileand partially hydrolyzing 1,2-dihydro-2-oxo-5-PY-nicotinonitrile toproduce 1,2-dihydro-2-oxo-5-PY-nicotinamide having the formula ##STR7##where PY is 4- or 3- or 2-pyridinyl or 4- or 3- or 2-pyridinyl havingone or two lower-alkyl substituents, and R₁ and R₂ are each lower-alkyl.8. The process according to claim 7 where PY is 4-pyridinyl.
 9. Theprocess which comprises the steps of heating1-R-1,2-dihydro-2-oxo-5-PY-nicotinonitrile or1-R-1,2-dihydro-2-oxo-5-PY-nicotinic acid with an aqueous mineral acidto produce 1-R-5-PY-2(1H)-pyridinone, reacting said1-R-5-PY-2(1H)-pyridinone with halogen to produce the corresponding1-R-3-halo-5-PY-2(1H)-pyridinone having the formula ##STR8## where PY is4- or 3- or 2-pyridinyl or 4- or 3- or 2-pyridinyl having one or twolower-alkyl substituents, R is hydrogen or lower-alkyl and Q is halo,and reacting said 3-halo compound with a lower-alkylamine or adi-(lower-alkyl)amine to produce the corresponding respective3-(lower-alkylamino)-5-PY-2(1H)-pyridinone or3-[di-(lower-alkyl)amino]-5-PY-2(1H)-pyridinone.